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1.
Neuroimage Clin ; 37: 103305, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36610310

RESUMO

INTRODUCTION: Lesion-symptom mapping is a key tool in understanding the relationship between brain structures and behavior. However, the behavioral consequences of lesions from different etiologies may vary because of how they affect brain tissue and how they are distributed. The inclusion of different etiologies would increase the statistical power but has been critically debated. Meanwhile, findings from lesion studies are a valuable resource for clinicians and used across different etiologies. Therefore, the main objective of the present study was to directly compare lesion-symptom maps for memory and language functions from two populations, a tumor versus a stroke population. METHODS: Data from two different studies were combined. Both the brain tumor (N = 196) and stroke (N = 147) patient populations underwent neuropsychological testing and an MRI, pre-operatively for the tumor population and within three months after stroke. For this study, we selected two internationally widely used standardized cognitive tasks, the Rey Auditory Verbal Learning Test and the Verbal Fluency Test. We used a state-of-the-art machine learning-based, multivariate voxel-wise approach to produce lesion-symptom maps for these cognitive tasks for both populations separately and combined. RESULTS: Our lesion-symptom mapping results for the separate patient populations largely followed the expected neuroanatomical pattern based on previous literature. Substantial differences in lesion distribution hindered direct comparison. Still, in brain areas with adequate coverage in both groups, considerable LSM differences between the two populations were present for both memory and fluency tasks. Post-hoc analyses of these locations confirmed that the cognitive consequences of focal brain damage varied between etiologies. CONCLUSION: The differences in the lesion-symptom maps between the stroke and tumor population could partly be explained by differences in lesion volume and topography. Despite these methodological limitations, both the lesion-symptom mapping results and the post-hoc analyses confirmed that etiology matters when investigating the cognitive consequences of lesions with lesion-symptom mapping. Therefore, caution is advised with generalizing lesion-symptom results across etiologies.


Assuntos
Neoplasias , Acidente Vascular Cerebral , Humanos , Mapeamento Encefálico/métodos , Acidente Vascular Cerebral/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Testes Neuropsicológicos , Imageamento por Ressonância Magnética/métodos , Neoplasias/patologia
2.
Clin Transl Radiat Oncol ; 31: 14-20, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34504960

RESUMO

PURPOSE: Numerous brain MR imaging studies have been performed to understand radiation-induced cognitive decline. However, many of them focus on a single region of interest, e.g. cerebral cortex or hippocampus. In this study, we use deformation-based morphometry (DBM) and voxel-based morphometry (VBM) to measure the morphological changes in patients receiving fractionated photon RT, and relate these to the dose. Additionally, we study tissue specific volume changes in white matter (WM), grey matter (GM), cerebrospinal fluid and total intracranial volume (TIV). METHODS AND MATERIALS: From our database, we selected 28 patients with MRI of high quality available at baseline and 1 year after RT. Scans were rigidly registered to each other, and to the planning CT and dose file. We used DBM to study non-tissue-specific volumetric changes, and VBM to study volume loss in grey matter. Observed changes were then related to the applied radiation dose (in EQD2). Additionally, brain tissue was segmented into WM, GM and cerebrospinal fluid, and changes in these volumes and TIV were tested. RESULTS: Performing DBM resulted in clusters of dose-dependent volume loss 1 year after RT seen throughout the brain. Both WM and GM were affected; within the latter both cerebral cortex and subcortical nuclei show volume loss. Volume loss rates ranging from 5.3 to 15.3%/30 Gy were seen in the cerebral cortical regions in which more than 40% of voxels were affected. In VBM, similar loss rates were seen in the cortex and nuclei. The total volume of WM and GM significantly decreased with rates of 5.8% and 2.1%, while TIV remained unchanged as expected. CONCLUSIONS: Radiotherapy is associated with dose-dependent intracranial morphological changes throughout the entire brain. Therefore, we will consider to revise sparing of organs at risk based on future cognitive and neurofunctional data.

3.
Phys Med Biol ; 66(8)2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33761491

RESUMO

A synthetic computed tomography (sCT) is required for daily plan optimization on an MRI-linac. Yet, only limited information is available on the accuracy of dose calculations on sCT for breast radiotherapy. This work aimed to (1) evaluate dosimetric accuracy of treatment plans for single-fraction neoadjuvant partial breast irradiation (PBI) on a 1.5 T MRI-linac calculated on a) bulk-density sCT mimicking the current MRI-linac workflow and b) deep learning-generated sCT, and (2) investigate the number of bulk-density levels required. For ten breast cancer patients we created three bulk-density sCTs of increasing complexity from the planning-CT, using bulk-density for: (1) body, lungs, and GTV (sCTBD1); (2) volumes for sCTBD1plus chest wall and ipsilateral breast (sCTBD2); (3) volumes for sCTBD2plus ribs (sCTBD3); and a deep learning-generated sCT (sCTDL) from a 1.5 T MRI in supine position. Single-fraction neoadjuvant PBI treatment plans for a 1.5 T MRI-linac were optimized on each sCT and recalculated on the planning-CT. Image evaluation was performed by assessing mean absolute error (MAE) and mean error (ME) in Hounsfield Units (HU) between the sCTs and the planning-CT. Dosimetric evaluation was performed by assessing dose differences, gamma pass rates, and dose-volume histogram (DVH) differences. The following results were obtained (median across patients for sCTBD1/sCTBD2/sCTBD3/sCTDLrespectively): MAE inside the body contour was 106/104/104/75 HU and ME was 8/9/6/28 HU, mean dose difference in the PTVGTVwas 0.15/0.00/0.00/-0.07 Gy, median gamma pass rate (2%/2 mm, 10% dose threshold) was 98.9/98.9/98.7/99.4%, and differences in DVH parameters were well below 2% for all structures except for the skin in the sCTDL. Accurate dose calculations for single-fraction neoadjuvant PBI on an MRI-linac could be performed on both bulk-density and deep learning sCT, facilitating further implementation of MRI-guided radiotherapy for breast cancer. Balancing simplicity and accuracy, sCTBD2showed the optimal number of bulk-density levels for a bulk-density approach.


Assuntos
Terapia Neoadjuvante , Humanos , Imageamento por Ressonância Magnética , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Tomografia Computadorizada por Raios X
4.
Radiat Oncol ; 14(1): 92, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31167658

RESUMO

Magnetic Resonance-guided radiotherapy (MRgRT) marks the beginning of a new era. MR is a versatile and suitable imaging modality for radiotherapy, as it enables direct visualization of the tumor and the surrounding organs at risk. Moreover, MRgRT provides real-time imaging to characterize and eventually track anatomical motion. Nevertheless, the successful translation of new technologies into clinical practice remains challenging. To date, the initial availability of next-generation hybrid MR-linac (MRL) systems is still limited and therefore, the focus of the present preview was on the initial applicability in current clinical practice and on future perspectives of this new technology for different treatment sites.MRgRT can be considered a groundbreaking new technology that is capable of creating new perspectives towards an individualized, patient-oriented planning and treatment approach, especially due to the ability to use daily online adaptation strategies. Furthermore, MRL systems overcome the limitations of conventional image-guided radiotherapy, especially in soft tissue, where target and organs at risk need accurate definition. Nevertheless, some concerns remain regarding the additional time needed to re-optimize dose distributions online, the reliability of the gating and tracking procedures and the interpretation of functional MR imaging markers and their potential changes during the course of treatment. Due to its continuous technological improvement and rapid clinical large-scale application in several anatomical settings, further studies may confirm the potential disruptive role of MRgRT in the evolving oncological environment.


Assuntos
Imageamento por Ressonância Magnética , Neoplasias/radioterapia , Radioterapia Guiada por Imagem , Humanos , Neoplasias/diagnóstico por imagem , Órgãos em Risco/diagnóstico por imagem , Órgãos em Risco/efeitos da radiação , Medicina de Precisão , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia Guiada por Imagem/tendências , Radioterapia de Intensidade Modulada , Reprodutibilidade dos Testes
5.
Clin Transl Radiat Oncol ; 14: 1-7, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30406210

RESUMO

BACKGROUND: In selected patients with early-stage and low-risk breast cancer, an MRI-linac based treatment might enable a radiosurgical, non-invasive alternative for current standard breast conserving therapy. AIM: To investigate whether single dose accelerated partial breast (APBI) to the intact tumor in both the prone and supine radiotherapy positions on the MRI-linac is dosimetrically feasible with respect to predefined coverage and organs at risk (OAR) constraints. MATERIAL & METHODS: For 20 patients with cTis or low-risk cT1N0M0 non-lobular breast carcinoma, previously treated with single dose preoperative APBI in the supine (n = 10) or prone (n = 10) position, additional intensity modulated radiotherapy plans with 7 coplanar beams in the presence of a 1.5T magnetic field were generated. A 20 Gy and 15 Gy dose was prescribed to the gross tumor and clinical target volume, respectively. The percentage of plans achieving predefined organ at risk (OAR) constraints, currently used in clinical practice, was assessed. Dosimetry differences between the prone versus supine approach and the MRI-linac versus clinically delivered plans were evaluated. RESULTS: All MRI-linac plans met the coverage and predefined OAR constraints. The prone approach appeared to be more favorable with respect to the chest wall, and ipsilateral lung dose compared to the supine position. No dosimetric differences were observed for the ipsilateral breast. No treatment position was clearly more beneficial for the skin or heart, since dosimetry varied among parameters. Overall, the MRI-linac and clinical plans were comparable, with minor absolute dosimetric differences. CONCLUSION: MRI-linac based single dose APBI to the intact tumor is a promising and a dosimetrically feasible strategy in patients with low-risk breast cancer. Preliminary OAR dosimetry favored the prone radiotherapy position.

6.
Radiother Oncol ; 126(3): 534-540, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28919003

RESUMO

BACKGROUND AND PURPOSE: The use of Stereotactic Body Radiotherapy (SBRT) for bone metastases is increasing rapidly. Therefore, knowledge of the inter-observer differences in tumor volume delineation is essential to guarantee precise dose delivery. The aim of this study is to compare inter-observer agreement in bone metastases delineated on different imaging modalities. MATERIAL AND METHODS: Twenty consecutive patients with bone metastases treated with SBRT were selected. All patients received CT and MR imaging in treatment position prior to SBRT. Five observers from three institutions independently delineated gross tumor volume (GTV) on CT alone, CT with co-registered MRI and MRI alone. Four contours per imaging modality per patient were available, as one set of contours was shared by 2 observers. Inter-observer agreement, expressed in generalized conformity index [CIgen], volumes of contours and contours center of mass (COM) were calculated per patient and imaging modality. RESULTS: Mean GTV delineated on MR (45.9±52.0cm3) was significantly larger compared to CT-MR (40.2±49.4cm3) and CT (34.8±41.8cm3). A considerable variation in CIgen was found on CT (mean 0.46, range 0.15-0.75) and CT-MRI (mean 0.54, range 0.17-0.71). The highest agreement was found on MRI (mean 0.56, range 0.20-0.77). The largest variations of COM were found in anterior-posterior direction for all imaging modalities. CONCLUSIONS: Large inter-observer variation in GTV delineation exists for CT, CT-MRI and MRI. MRI-based GTV delineation resulted in larger volumes and highest consistency between observers.


Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Neoplasias Ósseas/patologia , Estudos de Coortes , Humanos , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/normas , Variações Dependentes do Observador , Estudos Prospectivos , Radiocirurgia , Planejamento da Radioterapia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Tomografia Computadorizada por Raios X/normas , Carga Tumoral
7.
Phys Med Biol ; 62(23): L41-L50, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29135471

RESUMO

The integration of 1.5 T MRI functionality with a radiotherapy linear accelerator (linac) has been pursued since 1999 by the UMC Utrecht in close collaboration with Elekta and Philips. The idea behind this integrated device is to offer unrivalled, online and real-time, soft-tissue visualization of the tumour and the surroundings for more precise radiation delivery. The proof of concept of this device was given in 2009 by demonstrating simultaneous irradiation and MR imaging on phantoms, since then the device has been further developed and commercialized by Elekta. The aim of this work is to demonstrate the clinical feasibility of online, high-precision, high-field MRI guidance of radiotherapy using the first clinical prototype MRI-Linac. Four patients with lumbar spine bone metastases were treated with a 3 or 5 beam step-and-shoot IMRT plan. The IMRT plan was created while the patient was on the treatment table and based on the online 1.5 T MR images; pre-treatment CT was deformably registered to the online MRI to obtain Hounsfield values. Bone metastases were chosen as the first site as these tumors can be clearly visualized on MRI and the surrounding spine bone can be detected on the integrated portal imager. This way the portal images served as an independent verification of the MRI based guidance to quantify the geometric precision of radiation delivery. Dosimetric accuracy was assessed post-treatment from phantom measurements with an ionization chamber and film. Absolute doses were found to be highly accurate, with deviations ranging from 0.0% to 1.7% in the isocenter. The geometrical, MRI based targeting as confirmed using portal images was better than 0.5 mm, ranging from 0.2 mm to 0.4 mm. In conclusion, high precision, high-field, 1.5 T MRI guided radiotherapy is clinically feasible.


Assuntos
Neoplasias Ósseas/radioterapia , Região Lombossacral/efeitos da radiação , Imageamento por Ressonância Magnética/instrumentação , Aceleradores de Partículas/instrumentação , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Guiada por Imagem/métodos , Neoplasias da Coluna Vertebral/radioterapia , Idoso , Neoplasias Ósseas/secundário , Humanos , Pessoa de Meia-Idade , Imagens de Fantasmas , Radiometria , Dosagem Radioterapêutica , Neoplasias da Coluna Vertebral/patologia
8.
BMC Cancer ; 17(1): 181, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28274211

RESUMO

BACKGROUND: A shift towards less burdening and more patient friendly treatments for breast cancer is currently ongoing. In low-risk patients with early-stage disease, accelerated partial breast irradiation (APBI) is an alternative for whole breast irradiation following breast-conserving surgery. MRI-guided single dose ablative APBI has the potential to offer a minimally burdening, non-invasive treatment that could replace current breast-conserving therapy. METHODS: The ABLATIVE study is a prospective, single arm, multicenter study evaluating preoperative, single dose, ablative radiation treatment in patients with early-stage breast cancer. Patients with core biopsy proven non-lobular invasive breast cancer, (estrogen receptor positive, Her2 negative, maximum tumor size 3.0 cm on diagnostic MRI) and a negative sentinel node biopsy are eligible. Radiotherapy (RT) planning will be performed using a contrast enhanced (CE) planning CT-scan, co-registered with a CE-MRI, both in supine RT position. A total of twenty-five consecutive patients will be treated with a single ablative RT dose of 20 Gy to the tumor and 15 Gy to the tumorbed. Follow-up MRIs are scheduled within 1 week, 2, 4 and 6 months after single-dose RT. Breast-conserving surgery is scheduled at six months following RT. Primary study endpoint is pathological complete response. Secondary study endpoints are the radiological response and toxicity. Furthermore, patients will fill out questionnaires on quality of life and functional status. Cosmetic outcome will be evaluated by the treating radiation oncologist, patient and 'Breast Cancer Conservation Treatment cosmetic results' software. Recurrence and survival rates will be assessed. The patients will be followed up to 10 years after diagnosis. If patients give additional informed consent, a biopsy and a part of the irradiated specimen will be stored at the local Biobank and used for future research on radiotherapy response associated genotyping. DISCUSSION: The ABLATIVE study evaluates MRI-guided single dose ablative RT in patients with early-stage breast cancer, aiming at a less burdening and non-invasive alternative for current breast-conserving treatment. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT02316561 . The trial was registrated prospectively on October 10th 2014.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Radioterapia de Intensidade Modulada/métodos , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Pré-Operatórios , Estudos Prospectivos , Qualidade de Vida , Planejamento da Radioterapia Assistida por Computador , Tomografia Computadorizada por Raios X , Resultado do Tratamento
9.
Clin Oncol (R Coll Radiol) ; 28(12): e206-e215, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27692741

RESUMO

AIMS: Functional imaging with positron emission tomography/computed tomography (PET/CT) and multiparametric magnetic resonance (mpMR) is increasingly applied for radiotherapy purposes. However, evidence and experience are still limited, and this may lead to clinically relevant differences in accessibility, interpretation and decision making. We investigated the current patterns of care in functional imaging for radiotherapy in the Netherlands in a care evaluation study. MATERIALS AND METHODS: The availability of functional imaging in radiotherapy centres in the Netherlands was evaluated; features available in >80% of academic and >80% of non-academic centres were considered standard of care. The impact of functional imaging on clinical decision making was evaluated using case questionnaires on lung, head/neck, breast and prostate cancer, with multiple-choice questions on primary tumour delineation, nodal involvement, distant metastasis and incidental findings. Radiation oncologists were allowed to discuss cases in a multidisciplinary approach. Ordinal answers were evaluated by median and interquartile range (IQR) to identify the extent and variability of clinical impact; additional patterns were evaluated descriptively. RESULTS: Information was collected from 18 radiotherapy centres in the Netherlands (all except two). PET/CT was available for radiotherapy purposes to 94% of centres; 67% in the treatment position and 61% with integrated planning CT. mpMR was available to all centres; 61% in the treatment position. Technologists collaborated between departments to acquire PET/CT or mpMR for radiotherapy in 89%. All sites could carry out image registration for target definition. Functional imaging generally showed a high clinical impact (average median 4.3, scale 1-6) and good observer agreement (average IQR 1.1, scale 0-6). However, several issues resulted in ignoring functional imaging (e.g. positional discrepancies, central necrosis) or poor observer agreement (atelectasis, diagnostic discrepancies, conformation strategies). CONCLUSIONS: Access to functional imaging with PET/CT and mpMR for radiotherapy purposes, with collaborating technologists and multimodal delineation, can be considered standard of care in the Netherlands. For several specific clinical situations, the interpretation of images may benefit from further standardisation.


Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias/radioterapia , Países Baixos , Planejamento da Radioterapia Assistida por Computador/métodos , Inquéritos e Questionários
10.
Med Phys ; 43(7): 4375, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27370152

RESUMO

PURPOSE: The high precession frequency in ultrahigh field MRI coincides with reduced RF penetration, increased RF power deposition and consequently can lead to reduced scan efficiency. However, the shorter wavelength enables the use of efficient antennas rather than loop coils. In fact, ultrathin monopole antennas have been demonstrated at 7 T, which fit in natural cavities like the rectum in the human body. As the RF field generated by the antenna provides an extremely nonuniform B1 field, the use of conventional RF pulses will lead to severe image distortions and highly nonuniform contrast. However, using the two predominant dimensions (orthogonal to the antenna), 2D RF pulses can be designed that counteract the nonuniform B1 into uniform flip angles. In this study the authors investigate the use of an ultrathin antenna not only for reception, but also for transmission in 7 T MRI of the rectum. METHODS: The 2D radially compensating excitation (2D RACE) pulse was designed in matlab. SAR calculations between the 2D RACE pulse and an adiabatic RF pulse (BIR-4) have been obtained, to visualize the gain in decreasing the SAR when using the 2D RACE pulse instead of an adiabatic RF pulse. The authors used the 7 T whole body MR system in combination with an internally placed monopole antenna used for transceiving and obtained 3D gradient echo images with a conventional sinc pulse and with the 2D RACE pulse. For extra clarity, they also reconstructed an image where the receive field of the antenna was removed. RESULTS: Comparing the results of the SAR simulations of the 2D RACE pulse with a BIR-4 pulse shows that for low flip angles (θ < 41°) the SAR can be decreased with a factor of 4.8 or even more, when using the 2D RACE pulse. Relative to a conventional sinc excitation, the 2D RACE pulse achieves more uniform flip angle distributions than a BIR-4 pulse with a smaller SAR increase (16 × versus 64 ×). CONCLUSIONS: The authors have shown that the 2D RACE pulse provides more homogeneous flip angles for gradient echo sequences when compared to a conventional sinc pulse albeit at increased SAR. However, when compared to adiabatic RF pulses, as shown by simulations, the SAR of the 2D RACE pulse can be an order of magnitude less. Phantom and in vivo human rectum images are obtained to demonstrate that the 2D RACE pulse can provide a uniform excitation while transmitting with a single ultrathin endorectal antenna at 7 T. The combination of thin rectal antennas with efficient uniform transmit can open up new possibilities in high resolution imaging of rectal cancer.


Assuntos
Imageamento Tridimensional/instrumentação , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/instrumentação , Imageamento por Ressonância Magnética/métodos , Reto/diagnóstico por imagem , Algoritmos , Simulação por Computador , Desenho de Equipamento , Humanos , Modelos Anatômicos , Imagens de Fantasmas , Software
11.
Phys Med Biol ; 60(9): 3759-73, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25905452

RESUMO

Dynamic contrast enhanced CT (DCE-CT) can be used to estimate blood perfusion and vessel permeability in tumors. Tumor induced angiogenesis is generally associated with disorganized microvasculature with increased permeability or leakage. Estimated vascular leakage (K(trans)) values and their reliability greatly depend on the perfusion model used. To identify the preferred model for larynx tumor analysis, several perfusion models frequently used for estimating permeability were compared in this study. DCE-CT scans were acquired for 16 larynx cancer patients. Larynx tumors were delineated based on whole-mount histopathology after laryngectomy. DCE-CT data within these delineated volumes were analyzed using the Patlak and Logan plots, the Extended Tofts Model (ETM), the Adiabatic Approximation to the Tissue Homogeneity model (AATH) and a variant of AATH with fixed transit time (AATHFT). Akaike's Information Criterion (AIC) was used to identify the best fitting model. K(trans) values from all models were compared with this best fitting model. Correlation strength was tested with two-tailed Spearman's rank correlation and further examined using Bland-Altman plots. AATHFT was found to be the best fitting model. The overall median of individual patient medians K(trans) estimates were 14.3, 15.1, 16.1, 2.6 and 22.5 mL/100 g min( - 1) for AATH, AATHFT, ETM, Patlak and Logan, respectively. K(trans) estimates for all models except Patlak were strongly correlated (P < 0.001). Bland-Altman plots show large biases but no significant deviating trend for any model other than Patlak. AATHFT was found to be the preferred model among those tested for estimation of K(trans) in larynx tumors.


Assuntos
Algoritmos , Aumento da Imagem/métodos , Neoplasias Laríngeas/diagnóstico , Neovascularização Patológica/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Meios de Contraste , Humanos
12.
Neuropharmacology ; 77: 120-30, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24067928

RESUMO

Phosphodiesterase type 4 inhibitors (PDE4-Is) have received increasing attention as cognition-enhancers and putative treatment strategies for Alzheimer's disease (AD). By preventing cAMP breakdown, PDE4-Is can enhance intracellular signal transduction and increase the phosphorylation of cAMP response element-binding protein (CREB) and transcription of proteins related to synaptic plasticity and associated memory formation. Unfortunately, clinical development of PDE4-Is has been seriously hampered by emetic side effects. The new isoform-specific PDE4D-I, GEBR-7b, has shown to have beneficial effects on memory at non-emetic doses. The aim of the current study was to investigate chronic cognition-enhancing effects of GEBR-7b in a mouse model of AD. To this extent, 5-month-old (5M) APPswe/PS1dE9 mice received daily subcutaneous injections with GEBR-7b (0.001 mg/kg) or vehicle for a period of 3 weeks, and were tested on affective and cognitive behavior at 7M. We demonstrated a cognition-enhancing potential in APPswe/PS1dE9 mice as their spatial memory function at 7M in the object location test was improved by prior GEBR-7b treatment. APPswe/PS1dE9 mice displayed lower levels of CREB phosphorylation, which remained unaltered after chronic GEBR-7b treatment, and higher levels of tau in the hippocampus. Hippocampal brain-derived neurotrophic factor levels and synaptic densities were not different between experimental groups and no effects were observed on hippocampal GSK3ß and tau phosphorylation or Aß levels. In conclusion, GEBR-7b can enhance spatial memory function in the APPswe/PS1dE9 mouse model of AD. Although the underlying mechanisms of its cognition-enhancing potential remain to be elucidated, PDE4D inhibition appears an interesting novel therapeutic option for cognitive deficits in AD.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Hipocampo/efeitos dos fármacos , Iminas/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Morfolinas/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large , Guanilato Quinases/metabolismo , Hipocampo/metabolismo , Iminas/uso terapêutico , Proteínas de Membrana/metabolismo , Camundongos , Morfolinas/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Fosforilação/efeitos dos fármacos
13.
Strahlenther Onkol ; 189(2): 117-22, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23283590

RESUMO

BACKGROUND AND PURPOSE: The aim of this study was to assess the predictive potential of diffusion-weighted magnetic resonance imaging (MRI) for the selection of favorable pathological responders after radiochemotherapy for locally advanced rectal cancer. PATIENTS AND METHODS: In 59 patients with locally advanced rectal cancer, the apparent diffusion coefficient (ADC) in the tumor was obtained at 3 Tesla before radiochemotherapy and surgery. The predictive potential for pathological complete response (pCR) and good response (GR) was assessed. GR was defined as pCR and near-pCR based on the tumor regression grade. RESULTS: The GR group consisted of 13 patients (22%) with 9 complete responders. Both the preradiochemotherapy ADC values and relative change in ADC (ΔADC) were predictive for pathological response. Preradiochemotherapy ADC values showed a positive predictive value of 42% for pCR and 67% for GR using a similar cut-off value of 0.97(*)10(-3) mm(2)/s. For ΔADC, the optimal threshold for predicting GR or pCR was a 41% increase of the ADC. With this threshold, positive predictive values of 64% and 91% were found for pCR and GR, respectively. CONCLUSION: Low preradiochemotherapy ADC values and high ΔADC correspond to pathological good response. Diffusion-weighted MRI may be used as an additional tool for selecting good treatment responders after radiochemotherapy.


Assuntos
Quimiorradioterapia Adjuvante/métodos , Imagem de Difusão por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/métodos , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do Tratamento
14.
J Chem Neuroanat ; 46(1-2): 1-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23022956

RESUMO

Vagus nerve stimulation (VNS) is a moderately effective treatment for intractable epilepsy. However, the mechanism of action is poorly understood. The effect of left VNS in amygdala kindled rats was investigated by studying changes in nNOS and ΔFos B expression in primary and secondary vagus nerve projection nuclei: the nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus nerve (DMV), parabrachial nucleus (PBN) and locus coeruleus (LC). Rats were fully kindled by stimulation of the amygdala. Subsequently, when the fully kindled state was reached and then maintained for ten days, rats received a single 3-min train of VNS starting 1min prior to the kindling stimulus and lasting for 2min afterwards. In control animals the vagus nerve was not stimulated. Animals were sacrificed 48h later. The brainstems were stained for neuronal nitric oxide synthase (nNOS) and ΔFos B. VNS decreased seizure duration with more than 25% in 21% of rats. No VNS associated changes in nNOS immunoreactivity were observed in the NTS and no changes in ΔFos B were observed in the NTS, PBN, or LC. High nNOS immunopositive cell densities of >300cells/mm(2) were significantly more frequent in the left DMV than in the right (χ(2)(1)=26.2, p<0.01), independent of whether the vagus nerve was stimulated. We conclude that the observed nNOS immunoreactivity in the DMV suggests surgery-induced axonal damage. A 3-min train of VNS in fully kindled rats does not affect ΔFos B expression in primary and secondary projection nuclei of the vagus nerve.


Assuntos
Tronco Encefálico/metabolismo , Modelos Animais de Doenças , Óxido Nítrico Sintase Tipo I/biossíntese , Proteínas Proto-Oncogênicas c-fos/biossíntese , Convulsões/metabolismo , Estimulação do Nervo Vago/métodos , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Convulsões/terapia , Nervo Vago/metabolismo
15.
Med Phys ; 39(6Part6): 3665, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28517602

RESUMO

For radiotherapy, oesophageal cancer is located in a difficult area. Spatial control of the dose distribution is difficult to achieve with current CT-based radiation techniques, as on CT, soft-tissue contrast is too low. Furthermore, the oesophagus moves and organs at risk (e.g. lung, heart, liver, spinal cord) are in close proximity. An 1.5 T MRI-accelerator (MRL) has sufficient soft-tissue tumour visualization possibilities to allow for precise real-time, online, position verification and for dose escalation without organ at riskoverdose. Our research consists of the preparatory work for the first clinical study on the MRL for patients with oesophageal cancer. To improve image quality and reduce the motion artefacts, the benefit of cardiac triggering and breath holds is evaluated on fifteen oesophageal patients. Results show the superb image quality of these MRI sequences. The use of this high quality MRI gives the possibility for non-invasive real-time visualization andtracking of the tumour. We quantify oesophageal tumour motion on cineMRI. The tumour is tracked on sequential mixed T1/T2w images (acquisition time: 60s, temporal resolution: 0.5s, slice thickness: 7mm) of a single coronal and sagittal slice using a Minimum Output Sum of Squared Error (MOSSE) adaptive correlation filter. Tumour registration within the individual images can typically be done at a millisecond time scale. Motion of oesophageal tumours can well be tracked and is highly variable between patients. The greatest mobility is seen in cranio-caudal direction, with amaximum peak-to-peak amplitude of tumour movement of 24.5mm followed by the dorso-ventral and the medio-lateral direction. Movement seems greatest in tumours located in the lower part of the oesophagus. This study shows both the superb image quality for GTV localisation and the possibility for on-line and real time tumour tracking. The study opens thepossibility for tracked radiation delivery with a 1.5T MRI accelerator. Partial funding has been obtained by Elekta and Philips.

16.
Appl Magn Reson ; 38(3): 349-360, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20502507

RESUMO

The objective of this study is to assess whether ultrasmall superparamagnetic iron oxide (USPIO)-induced changes of the water proton longitudinal relaxation rate (R(1)) provide a means to assess blood hemodynamics of tumors. Two types of murine colon tumors (C26a and C38) were investigated prior to and following administration of USPIO blood-pool contrast agent with fast R(1) measurements. In a subpopulation of mice, R(1) was measured following administration of hydralazine, a well-known blood hemodynamic modifier. USPIO-induced R(1) increase in C38 tumors (DeltaR(1) = 0.072 +/- 0.0081 s(-1)) was significantly larger than in C26a tumors (DeltaR(1) = 0.032 +/- 0.0018 s(-1), N = 9, t test, P < 0.001). This was in agreement with the immunohistochemical data that showed higher values of relative vascular area (RVA) in C38 tumors than in C26a tumors (RVA = 0.059 +/- 0.015 vs. 0.020 +/- 0.011; P < 0.05). Following administration of hydralazine, a decrease in R(1) value was observed. This was consistent with the vasoconstriction induced by the steal effect mechanism. In conclusion, R(1) changes induced by USPIO are sensitive to tumor vascular morphology and to blood hemodynamics. Thus, R(1) measurements following USPIO administration can give novel insight into the effects of blood hemodynamic modifiers, non-invasively and with a high temporal resolution.

17.
MAGMA ; 17(3-6): 281-7, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15580375

RESUMO

The purpose of this study was to investigate the magnetic resonance imaging (MRI) characteristics of colon cancer metastases in rat liver at 7 T. A dedicated RF microstrip coil of novel design was built in order to increase the signal-to-noise ratio and, in combination with respiratory triggering, to minimize motion artifacts. T1- and T2-weighted MR imaging was performed to follow tumor growth. T1-weighted images provided a good anatomical delineation of the liver structure, while the best contrast between metastases and normal liver tissue was achieved with T2-weighted images. Measurements of T1 and T2 relaxation times were performed with inversion recovery FLASH and Carr-Purcell-Meiboom-Gill and inversion recovery FLASH imaging sequences, respectively, for quantitative MR characterization of metastases. Both the T1 and T2 of the metastases were significantly higher than those of normal liver tissue. Further, an increase in the T1 relaxation time of the metastases was observed with tumor growth. These findings suggest that quantitative in vivo MR characterization provides information on tumor development and possibly response to therapy, though additional studies are needed to elucidate the correlation between the changes in relaxation times and tumor microenvironment.


Assuntos
Carcinoma/patologia , Carcinoma/secundário , Neoplasias do Colo/patologia , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Masculino , Ratos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
18.
MAGMA ; 17(3-6): 303-12, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15614513

RESUMO

The aim of this study was to detect late radiation effects in the rat spinal cord using MR imaging with ultra-small particles of iron oxide (USPIO) contrast agent to better understand the development of late radiation damage with emphasis on the period preceding neurological signs. Additionally, the role of an inflammatory reaction was assessed by measuring macrophages that internalized USPIO. T2-weighted spin echo MR measurements were performed at 7T in six rats before paresis was expected (130-150 days post-irradiation, early group), and in six paretic rats (150-190 days post-irradiation, late group). Measurements were performed before, directly after and, only in the early group, 40 h after USPIO administration and compared with histology. In the early group, MR images showed focal regions in grey matter (GM) and white matter (WM) with signal intensity reduction after USPIO injection. Larger lesions with contrast enhancement were located in and around edematous GM of three animals of the early group and five of the late group. Forty hours after injection, additional lesions in WM, GM and nerve roots appeared in animals with GM edema. In the late paretic group, MR imaging showed WM necrosis adjacent to areas with large contrast enhancement. In conclusion, detection of early focal lesions was improved by contrast administration. In the animals with extended radiation damage, large hypo-intense regions appeared due to USPIO, which might be attributed to blood spinal cord barrier breakdown, but the involvement of blood-derived iron-loaded macrophages could not be excluded.


Assuntos
Ferro , Imageamento por Ressonância Magnética/métodos , Mielite/patologia , Óxidos , Lesões por Radiação/patologia , Medição de Risco/métodos , Medula Espinal/patologia , Medula Espinal/efeitos da radiação , Animais , Meios de Contraste , Dextranos , Óxido Ferroso-Férrico , Aumento da Imagem/métodos , Nanopartículas de Magnetita , Masculino , Mielite/etiologia , Lesões por Radiação/etiologia , Radioterapia/efeitos adversos , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Vértebras Torácicas/patologia , Vértebras Torácicas/efeitos da radiação
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