RESUMEN
BACKGROUND: [18F]flortaucipir (FTP) tau PET quantification is known to be affected by non-specific binding in off-target regions. Although partial volume correction (PVC) techniques partially account for this effect, their inclusion may also introduce noise and variability into the quantification process. While the impact of these effects has been studied in cross-sectional designs, the benefits and drawbacks of PVC on longitudinal FTP studies is still under scrutiny. The aim of this work was to study the performance of the most common PVC techniques for longitudinal FTP imaging. METHODS: A cohort of 247 individuals from the Alzheimer's Disease Neuroimaging Initiative with concurrent baseline FTP-PET, amyloid-beta (Aß) PET and structural MRI, as well as with follow-up FTP-PET and MRI were included in the study. FTP-PET scans were corrected for partial volume effects using Meltzer's, a simple and popular analytical PVC, and both the region-based voxel-wise (RBV) and the iterative Yang (iY) corrections. FTP SUVR values and their longitudinal rates of change were calculated for regions of interest (ROI) corresponding to Braak Areas I-VI, for a temporal meta-ROI and for regions typically displaying off-target FTP binding (caudate, putamen, pallidum, thalamus, choroid plexus, hemispheric white matter, cerebellar white matter, and cerebrospinal fluid). The longitudinal correlation between binding in off-target and target ROIs was analysed for the different PVCs. Additionally, group differences in longitudinal FTP SUVR rates of change between Aß-negative (A-) and Aß-positive (A+), and between cognitively unimpaired (CU) and cognitively impaired (CI) individuals, were studied. Finally, we compared the ability of different partial-volume-corrected baseline FTP SUVRs to predict longitudinal brain atrophy and cognitive decline. RESULTS: Among off-target ROIs, hemispheric white matter showed the highest correlation with longitudinal FTP SUVR rates from cortical target ROIs (R2=0.28-0.82), with CSF coming in second (R2=0.28-0.42). Application of voxel-wise PVC techniques minimized this correlation, with RBV performing best (R2=0.00-0.07 for hemispheric white matter). PVC also increased group differences between CU and CI individuals in FTP SUVR rates of change across all target regions, with RBV again performing best (No PVC: Cohen's d = 0.26-0.66; RBV: Cohen's d = 0.43-0.74). These improvements were not observed for differentiating A- from A+ groups. Additionally, voxel-wise PVC techniques strengthened the correlation between baseline FTP SUVR and longitudinal grey matter atrophy and cognitive decline. CONCLUSION: Quantification of longitudinal FTP SUVR rates of change is affected by signal from off-target regions, especially the hemispheric white matter and the CSF. Voxel-wise PVC techniques significantly reduce this effect. PVC provided a significant but modest benefit for tasks involving the measurement of group-level longitudinal differences. These findings are particularly relevant for the estimations of sample sizes and analysis methodologies of longitudinal group studies.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Encéfalo/metabolismo , Estudios Transversales , Enfermedad de Alzheimer/metabolismo , Estudios Longitudinales , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/patología , Tomografía de Emisión de Positrones/métodos , Atrofia/patología , Proteínas tau/metabolismoRESUMEN
PURPOSE: Recent evidence suggests that PET imaging with amyloid-ß (Aß) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer's disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aß PET, contributes to AD progression remains unexplored. METHODS: Participants with concurrent 18F-florbetapir (FBP) PET, MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aß-positive cognitively impaired, and 207 Aß-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images (n = 195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and fluid biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline. RESULTS: In AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aß, and WMH burden. Most of these associations were also observed in Aß-negative cognitively impaired individuals. CONCLUSION: These results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedades Desmielinizantes , Sustancia Blanca , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Compuestos de Anilina , Biomarcadores , Disfunción Cognitiva/patología , Estudios Transversales , Enfermedades Desmielinizantes/patología , Imagen de Difusión Tensora/métodos , Glicoles de Etileno , Humanos , Vaina de Mielina/patología , Tomografía de Emisión de Positrones/métodos , Sustancia Blanca/metabolismo , Proteínas tauRESUMEN
OBJECTIVES: We aimed at investigating the origin of the correlations between tumor volume and 18F-FDG-PET texture indices in lung cancer. METHODS: Eighty-five consecutive patients with newly diagnosed non-small cell lung cancer (NSCLC) underwent a 18F-FDG-PET/CT scan before treatment. Seven phantom spheres uniformly filled with 18F-FDG, and covering a range of activities and volumes similar to that found in lung tumors, were also scanned. Established texture indices were computed for lung tumors and homogeneous spheres. The dependence between textural indices and volume in homogeneous spheres was modeled and then used to predict texture indices in lung tumors. Correlation analyses were carried out between predicted and texture features measured in lung tumors. Cox proportional hazards regression was used to investigate the associations between overall survival and volume-adjusted textural features. RESULTS: All textural features showed strong, non-linear correlations with volume, both in tumors and homogeneous spheres. Correlations between predicted versus measured texture features were very high for contrast (r2 = 0.91), dissimilarity (r2 = 0.90), ZP (r2 = 0.90), GLNN (r2 = 0.86), and homogeneity (r2 = 0.82); high for entropy (r2 = 0.50) and HILAE (r2 = 0.53); and low for energy (r2 = 0.30). Cox regressions showed that among volume-adjusted features, only HILAE was associated with overall survival (b = - 0.35, p = 0.008). CONCLUSION: We have shown that texture indices previously found to be correlated with a number of clinically relevant outcomes might not provide independent information apart from that driven by their correlation with tumor volume, suggesting that these metrics might not be suitable as intratumor heterogeneity markers. KEY POINTS: ⢠Associations between texture FDG-PET indices and overall survival have been widely reported in lung cancer, with tumor volume also being associated with overall survival, and therefore, it is still unclear whether the predictive power of textural indices is simply driven by this correlation. ⢠Our results demonstrated strong non-linear correlations between textural indices and volume, showing an analogous behavior for lung tumors from patients and homogeneous spheres inserted in phantoms. ⢠Our findings showed that texture FDG-PET indices might not provide independent information apart from that driven by their correlation with tumor volume.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de PositronesRESUMEN
The association between white matter hyperintensities (WMH) and amyloid accumulation over time in cognitively normal, amyloid-negative elderly people remains largely unexplored. In order to study whether baseline WMH were associated with longitudinal subthreshold amyloid accumulation, 159 cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative who were amyloid-negative at baseline were examined. All the participants underwent a T1 and a Fluid-Attenuated Inversion Recovery MRI scan at baseline. Amyloid PET imaging was performed at baseline and follow-up visits in 2-year intervals for up to 8 years. Partial volume correction was applied for quantifying cortical Standardised Uptake Value Ratios (SUVR). The associations between global and regional WMH burden and amyloid accumulation were assessed using linear mixed models adjusted by demographic characteristics and baseline SUVR. Partial volume correction increased the measured annual rate of change (+2.4%) compared to that obtained from non-corrected data (+0.5%). There were no significant correlations between baseline WMHs and baseline subthreshold cortical amyloid uptake. In a longitudinal analysis, increased baseline cortical SUVR and increased baseline burden of global (p â= â0.006), frontal (p â= â0.006), and parietal WMH (p â= â0.003) were associated with faster amyloid accumulation. WMH-related amyloid accumulation occurred in parietal, frontal, and, to a lesser extent, cingulate cortices. These results remained unchanged after a sensitivity analysis excluding participants with the highest cortical SUVRs. This is the first study to identify a specific spatial distribution of WMH which is associated with future amyloid accumulation in cognitively normal elderly subjects without PET-detectable amyloid pathology. These findings may have important implications in prevention trials for the early identification of amyloid accumulation.
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Amiloide/metabolismo , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/metabolismo , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Estudios Transversales , Reacciones Falso Positivas , Femenino , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/metabolismo , Humanos , Leucoaraiosis/diagnóstico por imagen , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Lóbulo Parietal/diagnóstico por imagen , Lóbulo Parietal/metabolismo , Tomografía de Emisión de Positrones , Valores de ReferenciaRESUMEN
BACKGROUND: The lack of standardization of intensity normalization methods and its unknown effect on the quantification output is recognized as a major drawback for the harmonization of brain FDG-PET quantification protocols. The aim of this work is the ground truth-based evaluation of different intensity normalization methods on brain FDG-PET quantification output. METHODS: Realistic FDG-PET images were generated using Monte Carlo simulation from activity and attenuation maps directly derived from 25 healthy subjects (adding theoretical relative hypometabolisms on 6 regions of interest and for 5 hypometabolism levels). Single-subject statistical parametric mapping (SPM) was applied to compare each simulated FDG-PET image with a healthy database after intensity normalization based on reference regions methods such as the brain stem (RRBS), cerebellum (RRC) and the temporal lobe contralateral to the lesion (RRTL), and data-driven methods, such as proportional scaling (PS), histogram-based method (HN) and iterative versions of both methods (iPS and iHN). The performance of these methods was evaluated in terms of the recovery of the introduced theoretical hypometabolic pattern and the appearance of unspecific hypometabolic and hypermetabolic findings. RESULTS: Detected hypometabolic patterns had significantly lower volumes than the introduced hypometabolisms for all intensity normalization methods particularly for slighter reductions in metabolism . Among the intensity normalization methods, RRC and HN provided the largest recovered hypometabolic volumes, while the RRBS showed the smallest recovery. In general, data-driven methods overcame reference regions and among them, the iterative methods overcame the non-iterative ones. Unspecific hypermetabolic volumes were similar for all methods, with the exception of PS, where it became a major limitation (up to 250 cm3) for extended and intense hypometabolism. On the other hand, unspecific hypometabolism was similar far all methods, and usually solved with appropriate clustering. CONCLUSIONS: Our findings showed that the inappropriate use of intensity normalization methods can provide remarkable bias in the detected hypometabolism and it represents a serious concern in terms of false positives. Based on our findings, we recommend the use of histogram-based intensity normalization methods. Reference region methods performance was equivalent to data-driven methods only when the selected reference region is large and stable.
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Mapeo Encefálico , Encéfalo/patología , Procesamiento de Imagen Asistido por Computador , Tomografía de Emisión de Positrones , Anciano , Mapeo Encefálico/métodos , Simulación por Computador , Femenino , Fluorodesoxiglucosa F18/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Radiofármacos/metabolismo , Lóbulo Temporal/patologíaRESUMEN
Intracerebral hemorrhage (ICH), being the most severe cerebrovascular disease, accounts for 10-15% of all strokes. Hematoma expansion is one of the most important factors associated with poor outcome in intracerebral hemorrhage (ICH). Several studies have suggested that an "ischemic penumbra" might arise when the hematoma has a large expansion, but clinical studies are inconclusive. We performed a preclinical study to demonstrate the presence of hypoxic-ischemic tissue around the hematoma by means of longitudinal [18F]-fluoromisonidazole ([18F]-FMISO) PET/MRI studies over time in an experimental ICH model. Our results showed that all [18F]-FMISO PET/MRI images exhibited hypoxic-ischemic tissue around the hematoma area. A significant increase of [18F]-FMISO uptake was found at 18-24 h post-ICH when the maximum of hematoma volume is achieved and this increase disappeared before 42 h. These results demonstrate the presence of hypoxic tissue around the hematoma and open the possibility of new therapies aimed to reduce ischemic damage associated with ICH.
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Hemorragia Cerebral/complicaciones , Hematoma/diagnóstico , Hipoxia-Isquemia Encefálica/diagnóstico , Misonidazol/análogos & derivados , Accidente Cerebrovascular/prevención & control , Anciano , Animales , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/patología , Modelos Animales de Enfermedad , Hematoma/etiología , Hematoma/patología , Humanos , Hipoxia-Isquemia Encefálica/etiología , Hipoxia-Isquemia Encefálica/patología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Misonidazol/administración & dosificación , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Ratas , Accidente Cerebrovascular/etiologíaRESUMEN
Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy (PELD)) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7. For years, different authors have reported cases of congenital generalized lipodystrophy due to the variant c.974dupG in BSCL2 associated with neurological manifestations of variable severity, although some of them clearly superimposable to PELD. To identify the molecular mechanisms responsible for these neurological alterations in two patients with c.974dupG. Clinical characterization, biochemistry, and neuroimaging studies of two girls carrying this variant. In silico analysis, PCR amplification, and BSCL2 cDNA sequencing. BSCL2-201 transcript expression, which lacks exon 7, by qPCR in fibroblasts from the index case, from a healthy child as a control and from two patients with PELD, and in leukocytes from the index case and her parents. One with a severe encephalopathy including a picture of intellectual deficiency, severe language impairment, myoclonic epilepsy, and lipodystrophy as described in PELD, dying at 9 years and 9 months of age. The other 2-year-old patient showed incipient signs of neurological involvement. In silico and cDNA sequencing studies showed that variant c.974dupG gives rise to skipping of exon 7. The expression of BSCL2-201 in fibroblasts was significantly higher in the index case than in the healthy child, although less than in the case with homozygous PELD due to c.985C>T variant. The expression of this transcript was approximately half in the healthy carrier parents of this patient. The c.974dupG variant leads to the skipping of exon 7 of the BSCL2 gene and is responsible for a variant of Celia's encephalopathy, with variable phenotypic expression.
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Encefalopatías/genética , Subunidades gamma de la Proteína de Unión al GTP/genética , Lipodistrofia Generalizada Congénita/genética , Enfermedades Neurodegenerativas/genética , Empalme Alternativo , Niño , Preescolar , ADN Complementario/genética , Exones , Resultado Fatal , Femenino , Fibroblastos/metabolismo , Variación Genética , Homocigoto , Humanos , Fenotipo , Análisis de Secuencia de ADNRESUMEN
PURPOSE: This study aims to determine whether PET textural features measured with a new dedicated breast PET scanner reflect biological characteristics of breast tumors. METHODS: One hundred and thirty-nine breast tumors from 127 consecutive patients were included in this analysis. All of them underwent a 18F-FDG PET scan before treatment. Well-known PET quantitative parameters such as SUV m a x , SUV m e a n , metabolically active tumor volume (MATV) and total lesion glycolysis (TLG) were extracted. Together with these parameters, local, regional, and global heterogeneity descriptors, which included five textural features (TF), were computed. Immunohistochemical classification of breast cancer considered five subtypes: luminal A like (LA), luminal B like/HER2 - (LB -), luminal B like/HER2+ (LB+), HER2-positive-non-luminal (HER2pnl), and triple negative (TN). Associations between PET features and tumor characteristics were assessed using non-parametric hypothesis tests. RESULTS: Along with well-established associations, new correlations were found. HER2-positive tumors had significantly higher uptake (p < 0.001, AUCs > 0.70) and presented different global and regional heterogeneity (p = 0.002, p = 0.016, respectively, AUCs < 0.70). Nine out of ten analyzed features were significantly associated with immunohistochemical subtype. Uptake was lower for LA tumors (p < 0.001) with AUCs ranging from 0.71 to 0.88 for each subgroup comparison. Heterogeneity metrics were significantly associated when comparing LA and LB - (p < 0.01), being regional heterogeneity metrics more discriminative than any other parameter (AUC = 0.80 compared to AUC = 0.71 for SUV). LB+ and HER2pnl tumors also showed more regional heterogeneity than LA tumors (AUCs = 0.79 and 0.84, respectively). After comparison with whole-body PET studies, we observed an overall improvement in the classification ability of both non-heterogeneity metrics and textural features. CONCLUSIONS: PET parameters extracted from high-resolution dedicated breast PET images showed new and stronger correlations with immunohistochemical factors and immunohistochemical subtype of breast cancer compared to whole-body PET.
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Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/metabolismo , Fluorodesoxiglucosa F18 , Procesamiento de Imagen Asistido por Computador , Tomografía de Emisión de Positrones , Relación Señal-Ruido , Neoplasias de la Mama/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The spinocerebellar ataxias (SCAs) form a clinically, genetically, and pathological heterogeneous group of autosomal-dominant degenerative diseases. In particular, SCA36 is characterized by a late-onset, slowly progressive cerebellar syndrome typically associated with sensorineural hearing loss. This study was aimed at analyzing the neurodegenerative process underlying SCA36 through fluorodeoxyglucose positron emission tomography (FDG-PET) and MRI scans. METHODS: Twenty SCA36 patients underwent a study consisting of FDG-PET and MRI scans. Clinical motor evaluation was performed through the Scale for the Assessment and Rating of Ataxia (SARA). FDG-PET was carried out using a voxel-by-voxel and region-of-interest analysis. MRI evaluation was based on visual inspection and volumetric analysis. RESULTS: SARA ranged from 0 to 24.5 (4 patients asymptomatic, 3 with unspecific symptoms, and 13 with cerebellar signs). FDG-PET revealed hypometabolism in the asymptomatic stage in the vermis and right cerebellar hemisphere. In the ataxic stage, hypometabolism spread to both cerebellar hemispheres and the brain stem. MRI was normal in asymptomatic and preataxic individuals and showed superior cerebellar vermis atrophy early in the ataxic stage, diffuse cerebellar atrophy some years into the disease course, and a pattern of olivopontocerebellar atrophy in the oldest patients. There was no significant cerebellar atrophy in patients younger than 50 years. CONCLUSIONS: We present the first FDG-PET study of SCA36 and one of the largest neuroimaging study of SCAs. Our results revealed neuronal dysfunctions in the vermis and right cerebellar hemisphere as soon as a decade before the onset of motor symptoms. In the ataxic stage, dysfunctions spread to both hemispheres and the brain stem. © 2016 International Parkinson and Movement Disorder Society.
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Tronco Encefálico/diagnóstico por imagen , Cerebelo/diagnóstico por imagen , Progresión de la Enfermedad , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones/métodos , Índice de Severidad de la Enfermedad , Ataxias Espinocerebelosas/diagnóstico , Adulto , Anciano , Tronco Encefálico/metabolismo , Tronco Encefálico/patología , Vermis Cerebeloso/diagnóstico por imagen , Vermis Cerebeloso/metabolismo , Vermis Cerebeloso/patología , Cerebelo/metabolismo , Cerebelo/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Nucleares , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/metabolismo , Ataxias Espinocerebelosas/patologíaRESUMEN
BACKGROUND: The aim of this study was to develop a method for estimating DMSA SPECT renal function on each renal pole in order to evaluate the effect of percutaneous nephrolithotripsy by focusing the measurements on the region through which the percutaneous approach is performed. METHODS: Twenty patients undergoing percutaneous nephrolithotripsy between November 2010 and June 2012 were included in this study. Both Planar and SPECT-DMSA studies were carried out before and after nephrolithotripsy. The effect of percutaneous nephrolithotripsy was evaluated by estimating the total renal function and the regional renal function of each renal pole. Despite PCNL has been previously reported as a minimally invasive technique, our results showed regional renal function decreases in the treated pole in most patients, affecting the total renal function in a few of them. RESULTS: A quantification method was used for estimating the SPECT DMSA renal function of the upper, interpolar and lower renal poles. Our results confirmed that total renal function was preserved after nephrolithotripsy. Nevertheless, the proposed method showed that the regional renal function of the treated pole decreased in most patients (15 of 20 patients), allowing us to find differences in patients who had not shown changes in the total renal function obtained from conventional quantification methods. CONCLUSION: A method for estimating the SPECT DMSA renal function focused on the treated pole enabled us to show for the first time that nephrolithotripsy can lead to a renal parenchymal damage restricted to the treated pole.
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Pruebas de Función Renal/métodos , Riñón/fisiopatología , Riñón/cirugía , Litotricia , Nefrostomía Percutánea , Succímero , Tomografía Computarizada de Emisión de Fotón Único , Femenino , Humanos , Riñón/diagnóstico por imagen , Cálculos Renales/diagnóstico por imagen , Cálculos Renales/fisiopatología , Cálculos Renales/cirugía , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
The last recommendations of the International Commission on Radiological Protection for eye lens dose suggest an important reduction on the radiation limits associated with early and late tissue reactions. The aim of this work is to quantify and optimize the eye lens dose associated to nurse staff during positron emission tomography (PET) procedures. PET is one of the most important diagnostic methods of oncological and neurological cancer disease involving an important number of workers exposed to the high energy isotope F-18. We characterize the relevant stages as preparation and administration of monodose syringes in terms of occupational dose. A direct reading silicon dosimeter was used to measure the lens dose to staff. The highest dose of radiation was observed during preparation of the fluorodesoxyglucose (FDG) syringes. By optimizing a suitable vials' distribution of FDG we find an important reduction in occupational doses. Extrapolation of our data to other clinical scenarios indicates that, depending on the work load and/or syringes activity, safety limits of the dose might be exceeded.
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Cristalino/efectos de la radiación , Personal de Enfermería en Hospital , Enfermedades Profesionales/etiología , Enfermedades Profesionales/prevención & control , Exposición Profesional/efectos adversos , Exposición Profesional/prevención & control , Tomografía de Emisión de Positrones , Protección Radiológica/normas , Fluorodesoxiglucosa F18/efectos adversos , Humanos , Dosis de Radiación , Radiometría , Radiofármacos/efectos adversosRESUMEN
Membranous CD44v6 levels in tumors and surrounding samples obtained from 94 patients with squamous cell lung carcinomas were studied and compared to clinical stage, cellular proliferation, membranous CD44v5 levels, epidermal growth factor receptor EGFR and cytoplasmatic concentrations of CYFRA 21.1. CD44v6 positive values were observed in 33/38 non-tumor samples and in 76/94 tumor samples, but there were not statistically significant differences between both subgroups. In CD44v6 positive tumor samples, CD44v6 was not associated with clinical stage, histological grade, ploidy and lymph node involvement, but significant association was found with high cellular proliferation. Likewise, CD44v6 positive tumors had significantly higher levels of EGFR and CD44v5. In patients with squamous cell lung carcinomas and clinical stage I, positive CD44v6 cases were associated with the same parameters. Furthermore, positive CD44v5 squamous tumors were associated significantly with histological grade III and lower levels of CYFRA21.1. Our findings support the value of CD44v6 as a possible indicator of poor outcome in patients with squamous lung carcinomas.
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Carcinoma de Células Escamosas/metabolismo , Membrana Celular/metabolismo , Receptores ErbB/metabolismo , Receptores de Hialuranos/metabolismo , Adulto , Anciano , Proliferación Celular/genética , Proliferación Celular/fisiología , Femenino , Humanos , Técnicas In Vitro , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Seipin/BSCL2 mutations can cause type 2 congenital generalised lipodystrophy (BSCL) or dominant motor neurone diseases. Type 2 BSCL is frequently associated with some degree of intellectual impairment, but not to fatal neurodegeneration. In order to unveil the aetiology and pathogenetic mechanisms of a new neurodegenerative syndrome associated with a novel BSCL2 mutation, six children, four of them showing the BSCL features, were studied. METHODS: Mutational and splicing analyses of BSCL2 were performed. The brain of two of these children was examined postmortem. Relative expression of BSCL2 transcripts was analysed by real-time reverse transcription-polymerase chain reaction (RT-PCR) in different tissues of the index case and controls. Overexpressed mutated seipin in HeLa cells was analysed by immunofluorescence and western blotting. RESULTS: Two patients carried a novel homozygous c.985C>T mutation, which appeared in the other four patients in compound heterozygosity. Splicing analysis showed that the c.985C>T mutation causes an aberrant splicing site leading to skipping of exon 7. Expression of exon 7-skipping transcripts was very high with respect to that of the non-skipped transcripts in all the analysed tissues of the index case. Neuropathological studies showed severe neurone loss, astrogliosis and intranuclear ubiquitin(+) aggregates in neurones from multiple cortical regions and in the caudate nucleus. CONCLUSIONS: Our results suggest that exon 7 skipping in the BSCL2 gene due to the c.985C>T mutation is responsible for a novel early onset, fatal neurodegenerative syndrome involving cerebral cortex and basal ganglia.
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Subunidades gamma de la Proteína de Unión al GTP/genética , Lipodistrofia Generalizada Congénita/genética , Mutación , Niño , Exones/genética , Resultado Fatal , Femenino , Subunidades gamma de la Proteína de Unión al GTP/química , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Genotipo , Células HeLa , Humanos , Lipodistrofia Generalizada Congénita/patología , Lipodistrofia Generalizada Congénita/fisiopatología , Masculino , Fenotipo , Empalme del ARN , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Breast cancer is currently becoming a disease of the elderly. We have studied the relation between CA 15.3 serum concentrations and clinical-pathological parameters in 69 women with IDC aged over 70 years (76.3±4.2; range: 71-88; median 76). A group of 205 women with the same tumor but aged <70 years (62.8±4.0; range: 55-70; median 63) was also considered for comparison. Tumor size, axillary lymph node involvement, distant metastasis and histological grade were taken account. Serum CA 15.3 was determined by luminescence assay. CA 15.3 serum concentrations ranged between 6 and 85 U/mL (median 22.9 U/mL), and were higher only in patients with greater (qualitative and quantitative; p: 0.041) tumor size. Our results show that in women with IDCs, and aged over 70 years, serum CA 15.3 serum concentrations are associated exclusively with a greater tumor size, being these findings different to those described in women with the same subtype of tumor considered as a whole or with lower age.
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Biomarcadores de Tumor/sangre , Neoplasias de la Mama/diagnóstico , Antígeno Carcinoembrionario/sangre , Carcinoma Ductal/diagnóstico , Mediciones Luminiscentes , Mucina-1/sangre , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Carcinoma Ductal/patología , Femenino , Humanos , Metástasis Linfática , Clasificación del TumorRESUMEN
Lung cancer accounts for the highest number of cancer-related deaths worldwide. Early diagnosis significantly increases the disease-free survival rate and a large amount of effort has been expended in screening trials and the development of early molecular diagnostics. However, a gold standard diagnostic strategy is not yet available. Here, based on miRNA expression profile in lung cancer and using a novel in silico reverse-transcriptomics approach, followed by analysis of the interactome; we have identified potential transcription factor (TF) markers that would facilitate diagnosis of subtype specific lung cancer. A subset of seven TF markers has been used in a microarray screen and was then validated by blood-based qPCR using stage-II and IV non-small cell lung carcinomas (NSCLC). Our results suggest that overexpression of HMGA1, E2F6, IRF1, and TFDP1 and downregulation or no expression of SUV39H1, RBL1, and HNRPD in blood is suitable for diagnosis of lung adenocarcinoma and squamous cell carcinoma sub-types of NSCLC. Here, E2F6 was, for the first time, found to be upregulated in NSCLC blood samples. The miRNA-TF-miRNA interaction based molecular mechanisms of these seven markers in NSCLC revealed that HMGA1 and TFDP1 play vital roles in lung cancer tumorigenesis. The strategy developed in this work is applicable to any other cancer or disease and can assist in the identification of potential biomarkers.
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Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Simulación por Computador , Perfilación de la Expresión Génica/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Transcripción Reversa/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Neoplasias Pulmonares/sangre , MicroARNs/genética , MicroARNs/metabolismo , Anotación de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Reproducibilidad de los Resultados , Carcinoma Pulmonar de Células Pequeñas/sangre , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Although many works have supported the utility of PET radiomics, several authors have raised concerns over the robustness and replicability of the results. This study aimed to perform a systematic review on the topic of PET radiomics and the used methodologies. METHODS: PubMed was searched up to 15 October 2020. Original research articles based on human data specifying at least one tumor type and PET image were included, excluding those that apply only first-order statistics and those including fewer than 20 patients. Each publication, cancer type, objective and several methodological parameters (number of patients and features, validation approach, among other things) were extracted. RESULTS: A total of 290 studies were included. Lung (28%) and head and neck (24%) were the most studied cancers. The most common objective was prognosis/treatment response (46%), followed by diagnosis/staging (21%), tumor characterization (18%) and technical evaluations (15%). The average number of patients included was 114 (median = 71; range 20-1419), and the average number of high-order features calculated per study was 31 (median = 26, range 1-286). CONCLUSIONS: PET radiomics is a promising field, but the number of patients in most publications is insufficient, and very few papers perform in-depth validations. The role of standardization initiatives will be crucial in the upcoming years.
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PURPOSE: SimPET (www.sim-pet.org) is a free cloud-based platform for the generation of realistic brain positron emission tomography (PET) data. In this work, we introduce the key features of the platform. In addition, we validate the platform by performing a comparison between simulated healthy brain FDG-PET images and real healthy subject data for three commercial scanners (GE Advance NXi, GE Discovery ST, and Siemens Biograph mCT). METHODS: The platform provides a graphical user interface to a set of automatic scripts taking care of the code execution for the phantom generation, simulation (SimSET), and tomographic image reconstruction (STIR). We characterize the performance using activity and attenuation maps derived from PET/CT and MRI data of 25 healthy subjects acquired with a GE Discovery ST. We then use the created maps to generate synthetic data for the GE Discovery ST, the GE Advance NXi, and the Siemens Biograph mCT. The validation was carried out by evaluating Bland-Altman differences between real and simulated images for each scanner. In addition, SPM voxel-wise comparison was performed to highlight regional differences. Examples for amyloid PET and for the generation of ground-truth pathological patients are included. RESULTS: The platform can be efficiently used for generating realistic simulated FDG-PET images in a reasonable amount of time. The validation showed small differences between SimPET and acquired FDG-PET images, with errors below 10% for 98.09% (GE Discovery ST), 95.09% (GE Advance NXi), and 91.35% (Siemens Biograph mCT) of the voxels. Nevertheless, our SPM analysis showed significant regional differences between the simulated images and real healthy patients, and thus, the use of the platform for converting control subject databases between different scanners requires further investigation. CONCLUSIONS: The presented platform can potentially allow scientists in clinical and research settings to perform MC simulation experiments without the need for high-end hardware or advanced computing knowledge and in a reasonable amount of time.
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Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones , Algoritmos , Encéfalo/diagnóstico por imagen , Humanos , Procesamiento de Imagen Asistido por Computador , Método de Montecarlo , Tomografía de Emisión de PositronesRESUMEN
PURPOSE: Preclinical dynamic brain PET studies remain hampered by the limitations related to the measurement of the arterial input function (AIF). In this regard, the use of an arterial-venous shunt is a promising method for the generation of real-time AIFs, but its application in longitudinal studies is still impeded by the cumbersome surgeries and high failure rates. We studied the feasibility and reproducibility of double arterial-venous shunt strategies for conducting longitudinal PET studies with real-time AIFs in rats. PROCEDURES: We studied the feasibility of double arterial-venous shunts in rats in the right/left inguinal region and evaluated inter-animal and intra-animal AIF reproducibilities. Image-derived input function (IDIF) was also obtained for comparison. Dynamic brain FDG PET studies were conducted to estimate kinetic constants and Cerebral Metabolic Rate of Glucose (CMRglc) obtained from standard 2-tissue compartment (2TCM) and Patlak analysis. RESULTS: We showed that longitudinal AIFs from double arterial-venous shunts can be obtained with very high success rate of the surgeries (88 %). Our results provided highly reproducible AIF measurements with low inter-animal variabilities (11 %) and intra-animal variabilities (5-10 %) that were included into the kinetic models, such that longitudinal rate constants and CMRglc can be efficiently estimated without bias associated to the double shunt. Our results indicated that longitudinal IDIF can be also generated without bias along time but showing higher intra-animal uncertainties. CONCLUSIONS: We have demonstrated the feasibility and high reproducibility of conducting longitudinal AIF measurements and consequently accurate kinetic modeling using arterial shunt method.
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Arterias/diagnóstico por imagen , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Circulación Cerebrovascular , Fluorodesoxiglucosa F18/farmacología , Tomografía de Emisión de Positrones/métodos , Animales , Derivación Arteriovenosa Quirúrgica , Glucemia/análisis , Estudios de Factibilidad , Cinética , Imagen por Resonancia Magnética , Masculino , Neuroimagen/métodos , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: To obtain individualized internal doses with a Monte Carlo (MC) method in patients undergoing diagnostic [18F]FCH-PET studies and to compare such doses with the MIRD method calculations. METHODS: A patient cohort of 17 males were imaged after intravenous administration of a mean [18F]FCH activity of 244.3 MBq. The resulting PET/CT images were processed in order to generate individualized input source and geometry files for dose computation with the MC tool GATE. The resulting dose estimates were studied and compared to the MIRD method with two different computational phantoms. Mass correction of the S-factors was applied when possible. Potential sources of uncertainty were closely examined: the effect of partial body images, urinary bladder emptying, and biokinetic modeling. RESULTS: Large differences in doses between our methodology and the MIRD method were found, generally in the range ±25%, and up to ±120% for some cases. The mass scaling showed improvements, especially for non-walled and high-uptake tissues. Simulations of the urinary bladder emptying showed negligible effects on doses to other organs, with the exception of the prostate. Dosimetry based on partial PET/CT images (excluding the legs) resulted in an overestimation of mean doses to bone, skin, and remaining tissues, and minor differences in other organs/tissues. Estimated uncertainties associated with the biokinetics of FCH introduce variations of cumulated activities in the range of ±10% in the high-uptake organs. CONCLUSIONS: The MC methodology allows for a higher degree of dosimetry individualization than the MIRD methodology, which in some cases leads to important differences in dose values. Dosimetry of FCH-PET based on a single partial PET study seems viable due to the particular biokinetics of FCH, even though some correction factors may need to be applied to estimate mean skin/bone doses.