Heterogeneous enhancement pattern in DCE-MRI reveals the morphology of normal lymph nodes: an experimental study

Purpose: To investigate the heterogeneous enhancement pattern in normal lymph nodes of healthy mice by different albumin-binding contrast agents. Methods: The enhancement of normal lymph nodes was assessed in mice by dynamic contrast-enhanced MRI (DCE-MRI) after the administration of two contrast agents characterized by different albumin-binding properties: gadopentetate dimeglumine (Gd-DTPA) and gadobenate dimeglumine (Gd-BOPTA). To take into account potential heterogeneities of the contrast uptake in the lymph nodes, k-means cluster analysis was performed on DCE-MRI data. Cluster spatial distribution was visually assessed. Statistical comparison among clusters and contrast agents was performed on semiquantitative parameters (AUC, wash-in rate, and wash-out rate) and on the relative size of the segmented clusters. Results: Cluster analysis of DCE-MRI data revealed at least two main clusters, localized in the outer portion and in the inner portion of each lymph node. With both contrast agents, AUC (p < 0.01) and wash-in (p < 0.05) rates were greater in the inner cluster, which also showed a steeper wash-out rate than the outer cluster (Gd-BOPTA, p < 0.01; Gd-DTPA, p=0.056). The size of the outer cluster was greater than that of the inner cluster by Gd-DTPA (p < 0.05) and Gd-BOPTA (p < 0.01). The enhancement pattern of Gd-DTPA was not significantly different from the enhancement pattern of Gd-BOPTA. Conclusion: DCE-MRI in normal lymph nodes shows a characteristic heterogeneous pattern, discriminating the periphery and the central portion of the lymph nodes. Such a pattern deserves to be investigated as a diagnostic marker for lymph node staging

Early Antiangiogenic Activity of SU11248 Evaluated <i>In vivo</i> by Dynamic Contrast-Enhanced Magnetic Resonance Imaging in an Experimental Model of Colon Carcinoma

Abstract Purpose: To compare two dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) techniques in terms of their ability in assessing the early antiangiogenic effect of SU11248, a novel selective multitargeted tyrosine kinase inhibitor, that exhibits direct antitumor and antiangiogenic activity via inhibition of the receptor tyrosine kinases platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and FLT3. Experimental Design: A s.c. tumor model of HT29 human colon carcinoma in athymic mice was used. Two DCE-MRI techniques were used based, respectively, on macromolecular [Gd-diethylenetriaminepentaacetic acid (DTPA)-albumin] and low molecular weight (Gd-DTPA) contrast agents. The first technique provided a quantitative measurement of transendothelial permeability and fractional plasma volume, accepted surrogate markers of tumor angiogenesis. With the second technique, we quantified the initial area under the concentration-time curve, which gives information related to tumor perfusion and vascular permeability. Experiments were done before and 24 hours after a single dose administration of SU11248. Results: The early antiangiogenic effect of SU11248 was detected by DCE-MRI with macromolecular contrast agent as a 42% decrease in vascular permeability measured in the tumor rim. The effect was also detected by DCE-MRI done with Gd-DTPA as a 31% decrease in the initial area under the concentration-time curve. Histologic slices showed a statistically significant difference in mean vessel density between the treated and control groups. Conclusions: The early antiangiogenic activity of SU11248 was detected in vivo by DCE-MRI techniques using either macromolecular or low molecular weight contrast agents. Because DCE-MRI techniques with low molecular weight contrast agents can be used in clinical studies, these results could be relevant for the design of clinical trials based on new paradigms

Learning approach to analyze tumour heterogeneity in DCE-MRI data during anti-cancer treatment

The paper proposes a learning approach to support medical researchers in the context of in-vivo cancer imaging, and specifically in the analysis of Dynamic Contrast-Enhanced MRI (DCE-MRI) data. Tumour heterogeneity is characterized by identifying regions with different vascular perfusion. The overall aim is to measure volume differences of such regions for two experimental groups: the treated group, to which an anticancer therapy is administered, and a control group. The proposed approach is based on a three-steps procedure: (i) robust features extraction from raw time-intensity curves, (ii) sample-regions identification manually traced by medical researchers on a small portion of input data, and (iii) overall segmentation by training a Support Vector Machine (SVM) to classify the MRI voxels according to the previously identified cancer areas. In this way a non-invasive method for the analysis of the treatment efficacy is obtained as shown by the promising results reported in our experiments. © 2009 Springer Berlin Heidelberg

Pilocarpine-Induced Status Epilepticus in Rats Involves Ischemic and Excitotoxic Mechanisms

The neuron loss characteristic of hippocampal sclerosis in temporal lobe epilepsy patients is thought to be the result of excitotoxic, rather than ischemic, injury. In this study, we assessed changes in vascular structure, gene expression, and the time course of neuronal degeneration in the cerebral cortex during the acute period after onset of pilocarpine-induced status epilepticus (SE). Immediately after 2 hr SE, the subgranular layers of somatosensory cortex exhibited a reduced vascular perfusion indicative of ischemia, whereas the immediately adjacent supragranular layers exhibited increased perfusion. Subgranular layers exhibited necrotic pathology, whereas the supergranular layers were characterized by a delayed (24 h after SE) degeneration apparently via programmed cell death. These results indicate that both excitotoxic and ischemic injuries occur during pilocarpine-induced SE. Both of these degenerative pathways, as well as the widespread and severe brain damage observed, should be considered when animal model-based data are compared to human pathology

Imaging multimodale in carcinomi sperimentali: il ruolo della componente stromale

I carcinomi presentano una struttura che riproduce quella dei tessuti normali ed è costituita da due compartimenti distinti ma dipendenti tra loro: il parenchima (formato da cellule neoplastiche di origine epiteliale) e lo stroma. Lo stroma è interposto tra le cellule maligne ed il tessuto normale dell’ospite, è essenziale per la crescita e la progressione del tumore, ed è prodotto dall’ospite mediante interazioni cellula-ospite. Lo stroma comprende tessuto di supporto non maligno che include plasma e proteine plasmatiche, varo tipo collagene interstiziale e fibrina. Inoltre comprende tre diversi tipi di cellule: cellule endoteliali, che costituiscono i vasi neoformati, cellule fibroblaste, che si trovano anche nel tessuto connettivo normale e cellule infiammatorie che provengono dal circolo sanguigno. I tumori solidi tra loro si differenziano in modo marcato per il contenuto di stroma e perfino all’interno del singolo tumore ci possono essere significative variazioni del contenuto stromale da un’area all’altra. Nel presente lavoro di tesi, diversi modelli di carcinomi sperimentali sono stati analizzati con tecniche di imaging in vivo - risonanza magnetica (RM) con mezzo di contrasto e tomografia a emissione di positroni (PET) dopo somministrazione di 2-fluoro-2-deossi-D-glucosio (FDG) – focalizzando l’attenzione sul compartimento stromale. L’indagine RM con mezzo di contrasto (sensibile alla vascolarizzazione tumorale) e PET-FDG (sensibile al metabolismo del glucosio) è stata integrata dall’analisi con tecniche di imaging ex vivo (istologia ed immunoistochimica). In particolare, la correlazione tra angiogenesi e metabolismo del glucosio è stata studiata per valutare la complementarietà, recentemente evidenziata nei carcinomi, tra la componente stromale e quella parenchimale. Infatti, è risaputo che le cellule maligne epiteliali sono caratterizzate da un metabolismo anaerobico, sia per l’elevato consumo di glucosio (effetto Warburg), sia per la frequente presenza di condizioni di ipossia. Nello stroma tumorale corrispondente, i fibroblasti hanno invece evidenziato un metabolismo prevalentemente aerobico, capace quindi di utilizzare i prodotti di scarto del metabolismo delle cellule tumorali, anche in virtù di una maggiore disponibilità di ossigeno fornita dalla componente vascolare annessa. Nel corso dello studio, tale complementarietà metabolica e la relativa diversa captazione alla PET-FDG è stata confermata dal confronto di due modelli di carcinomi sperimentali caratterizzati da una diversa estensione del volume stromale1 e validata con tecniche di immunoistochimica (con marcatori specifici per la neoangiogenesi e per il trasporto del glucosio). Su questi stessi modelli una diversa perfusione è stata confermata con mezzi di contrasto RM2, peraltro evidenziando anche un diverso riassorbimento (che avviene prevalentemente per via venosa, e non per via linfatica, come confermato da un altro studio su modelli di tumore mammario3). Nei tre modelli di tumore mammario (un carcinoma spontaneo, e un sarcoma ed un carcinoma sottocutanei derivati dal primo), caratterizzati per la loro differente vascolarizzazione, si è di nuovo osservato che la perfusione ed il metabolismo presentano caratteristiche di complementarietà, con zone più perfuse alla RM con mezzo di contrasto ma meno captanti alla PET-FDG e viceversa4. Gli effetti di questa organizzazione strettamente connessa con la componente stromale sono stati segnalati come possibile inconveniente quando si utilizza la PET-FDG da sola per la definizione dei margini tumorali nella pianificazione del trattamento radioterapico5. Infine, le caratteristiche della componente stromale sono state analizzate durante un trattamento anti-angiogenico6. L’analisi RM con mezzo di contrasto e l’analisi istologica hanno rivelato che la somministrazione prolungata di anti-angiogenici può promuovere lo sviluppo della componente stromale, che può avere un ruolo nella risposta adattiva del tumore a questi farmaci. In conclusione, gli studi effettuati su modelli sperimentali hanno evidenziano che la struttura compartimentale dei carcinomi, ovvero il parenchima delle cellule neoplastiche e la componente stromale associata, hanno una particolare corrispondenza con due delle due principali tecniche di imaging oncologico oggi disponibili. La complementarietà evidenziata (la RM con mezzo di contrasto è sensibile alla perfusione della componente stromale e la PET-FDG è sensibile al metabolismo della componente parenchimale) ne suggerisce un uso combinato. Inoltre, con la RM perfusionale è stato possibile studiare sia meccanismi di riassorbimento del mezzo di contrasto, sia le trasformazioni emerse durante terapia antiangiogenica. Si prevede che le osservazioni riportate, se confermate in ambito clinico, possano avere sviluppi nella diagnosi, nella definizione del trattamento e nel monitoraggio terapeutico dei carcinomi, e possano comunque essere utilizzate in ambito sperimentale visto il ruolo emergente che sta assumendo la componente stromale per comprendere la progressione tumorale e quindi per sviluppare nuovi e specifici trattamenti farmacologici.Carcinomas have a distinct structure which mimics that of normal tissues and comprises two distinct but interdependent compartments: the parenchyma (neoplastic cells) and the stroma. Stroma is interposed between malignant cells and normal host tissues and is essential for tumor growth. Stroma is largely a product of the host and its development is induced by tumor cell-host interactions. Thus, it comprises nonmalignant supporting tissue and includes leaked plasma and plasma proteins, interstitial collagens and fibrin. Moreover it includes three types of cells: endothelial cells forming new blood vessels, fibroblasts that reside also in normal connective tissue, and inflammatory cells that are derived from the blood. Tumors markedly differ from each other in quantitative stromal content, with significant variations in stromal composition from one area to another even within a single tumor. In this thesis different carcinoma models were analyzed in vivo - by contrast enhanced magnetic resonance imaging (MRI), and by (18)F-fluorodeoxy-glucose (FDG) positron emission tomography (PET) - focusing on the role of the stromal compartment. Since contrast enhanced MRI and FDG-PET are sensitive to tumor angiogenesis and glucose metabolism respectively, our studies investigated the correlation between perfusion and glucose metabolism. The same tumor models were also evaluated ex vivo - by histology and immunohistochemistry techniques. It is well known that cancer cells are characterized by anaerobic metabolism with high glucose consumption, both in hypoxic condition and even in high oxygen tension (Warburg effect). On the other hand, it has been recently reported that in carcinomas a complementary metabolism does exist between the epithelial neoplastic cells and the stromal fibroblasts. In fact, stromal fibroblasts have shown aerobic metabolism, consistent with higher oxygen availability due to the associated vascular supply, and the capability of buffering and recycling products of anaerobic metabolism to sustain cancer cell survival. In the present thesis, the complementary stromal/epithelial metabolism was confirmed by the resulting different FDG-uptake in two carcinoma models characterized by a markedly different stromal content1. These findings were also supported by immunohistochemical examination with markers specific for neoangiogenesis and glucose transporters. On the same experimental models, a corresponding different perfusion was observed by contrast enhanced MRI2. The different distribution of the contrast agents proved to be related to stromal content, which presumably produced also a different washout pattern of the contrast agent itself. Consistently, in an additional study on experimental mammary tumors, we demonstrated that the washout of the contrast agents mainly occurs by the venous system and not by lymphatic vessels3. Moreover, three different breast tumor models (a spontaneous and an implanted carcinoma, and a mesenchymal tumor), characterized by different vascularization, were evaluated. In these models perfusion and metabolism resulted to be complementary: tumors (and tumor areas) that were characterized by higher MR contrast enhancement showed lower FDG-uptake and vice-versa4. Such effect could constitute a potential risk of tumor volume underestimation when FDGPET is used as a single imaging modality to assess tumor boundaries and to delineate the target volume in radiotherapy planning5. Finally, tumor stroma evolution was assessed during antiangiogenic therapy6. Contrast enhanced MRI and histology revealed that prolonged treatment could promote an abnormal stromal development at the periphery of carcinomas, suggesting that cancer-associated stroma can have a role in the adaptive response to treatment. In conclusion, the reported studies on experimental models showed that the compartmental architecture of carcinomas, i.e. the neoplastic cell and the cancer-associated stroma, affects the sensitivity of two major cancer imaging methods, contrast enhanced MRI and FDG-PET. Contrast enhanced MRI appeared more sensitive to the presence of cancer-associated stroma due to perfusion. FDG-PET appeared more sensitive to the presence of cancer cells, due to glucose metabolism. This “complementary sensitivity” suggests a combined application of the two modalities for a comprehensive evaluation of carcinomas. Furthermore, the contrast enhanced MRI modality allowed to evaluate both washout mechanisms and the stromal modifications occurring during antiangiogenic therapy. The reported findings, if confirmed in clinical studies, could be applied in diagnosis, treatment planning and therapy assessment of human carcinomas. In any case they are relevant in experimental studies considering the emerging role of cancer-associated stroma to understand cancer progression and eventually to develop new targeted therapies

Combining low-dose radiation therapy and magnetic resonance guided focused ultrasound to reduce Amyloid-β deposition in Alzheimer's Disease

Amyloid-β deposition is one of the neuropathological hallmarks of Alzheimer's disease (AD), but pharmacological strategies toward its reduction are poorly effective.Preclinical studies indicate that low-dose radiation therapy (LD-RT) may reduce brain amyloid-β. Animal models and proof-of-concept preliminary data in humans have shown that magnetic resonance guided focused ultrasound (MRgFUS) can reversibly open the blood-brain-barrier and facilitate the delivery of targeted therapeutics to the hippocampus, to reduce amyloid-β and promote neurogenesis in AD. Ongoing clinical trials on AD are exploring whole-brain LD-RT, which may damage radio-sensitive structures, i.e., hippocampus and white matter, thus contributing to reduced neurogenesis and radiation-induced cognitive decline. However, selective irradiation of cortical amyloid-β plaques through advanced LD-RT techniques might spare the hippocampus and white matter. We propose combined use of advanced LD-RT and targeted drug delivery through MRgFUS for future clinical trials to reduce amyloid-β deposition in AD since its preclinical stages

Sparse deconvolution of proton radiography data to estimate water equivalent thickness maps

Purpose In proton therapy, the conversion of the planning computed tomography (CT) into proton stopping powers is tainted by uncertainties which may jeopardize dose conformity. Proton radiography provides a direct information on the energy reduction of protons in the patient. However, it is currently limited by the degradation (“blurring”) of the one‐dimensional depth‐dose deposition profiles which constitute the pixels. Methods An iterative algorithm is implemented to extract high‐resolution water equivalent thickness (WET) maps from the measurements of depth‐dose profiles acquired with a multilayer ionization chamber. The method relies on the assumption that those curves are a function of the WET, which can benefit from a sparse representation. Results When used without relying on any prior knowledge derived from the planning CT, the method already outperforms the published one in terms of accuracy. We also propose a variant which integrates the planning CT in a robust fashion to further improve the deconvolution result and reach an accuracy of 1.5 mm on the estimated WET. The methods are applied to both synthetic data and actual proton radiography acquisitions on phantoms. Conclusions Besides the increase in accuracy achieved in the estimation of WET maps from proton radiography data, we demonstrate that the proposed deconvolution algorithm is also more robust with respect to confounding factors such as residual setup errors or changes in the anatomy. Therefore, proton radiography using a range probe provides both the required accuracy to assess and reduce range uncertainty in proton therapy and the simplicity of integrated‐mode proton radiography

Pencil beam proton radiography using a multilayer ionization chamber

A pencil beam proton radiography (PR) method, using a commercial multilayer ionization chamber (MLIC) integrated with a treatment planning system (TPS) was developed. A Giraffe (IBA Dosimetry) MLIC (+/- 0.5 mm accuracy) was used to obtain pencil beam PR by delivering spots uniformly positioned at a 5.0 mm distance in a 9 x 9 square of spots. PRs of an electron-density (with tissue-equivalent inserts) phantom and a head phantom were acquired. The integral depth dose (IDD) curves of the delivered spots were computed by the TPS in a volume of water simulating the MLIC, and virtually added to the CT at the exit side of the phantoms. For each spot, measured and calculated IDD were overlapped in order to compute a map of range errors. On the head-phantom, the maximum dose from PR acquisition was estimated. Additionally, on the head phantom the impact on the range errors map was estimated in case of a 1 mm position misalignment. In the electron-density phantom, range errors were within 1 mm in the soft-tissue rods, but greater in the dense-rod. In the head-phantom the range errors were -0.9 +/- 2.7 mm on the whole map and within 1 mm in the brain area. On both phantoms greater errors were observed at inhomogeneity interfaces, due to sensitivity to small misalignment, and inaccurate TPS dose computation. The effect of the 1 mm misalignment was clearly visible on the range error map and produced an increased spread of range errors (-1.0 +/- 3.8 mm on the whole map). The dose to the patient for such PR acquisitions would be acceptable as the maximum dose to the head phantom was By the described 2D method, allowing to discriminate misalignments, range verification can be performed in selected areas to implement an in vivo quality assurance program

Technical Note:A direct ray-tracing method to compute integral depth dose in pencil beam proton radiography with a multilayer ionization chamber

Purpose: To introduce a fast ray-tracing algorithm in pencil proton radiography (PR) with a multilayer ionization chamber (MLIC) for in vivo range error mapping. Methods: Pencil beam PR was obtained by delivering spots uniformly positioned in a square (45x45 mm(2) field-of-view) of 9x9 spots capable of crossing the phantoms (210 MeV). The exit beam was collected by a MLIC to sample the integral depth dose (IDDMLIC). PRs of an electron-density and of a head phantom were acquired by moving the couch to obtain multiple 45x45 mm2 frames. To map the corresponding range errors, the two-dimensional set of IDDMLIC was compared with (i) the integral depth dose computed by the treatment planning system (TPS) by both analytic (IDDTPS) and Monte Carlo (IDDMC) algorithms in a volume of water simulating the MLIC at the CT, and (ii) the integral depth dose directly computed by a simple ray-tracing algorithm (IDDdirect) through the same CT data. The exact spatial position of the spot pattern was numerically adjusted testing different in-plane positions and selecting the one that minimized the range differences between IDDdirect and IDDMLIC. Results: Range error mapping was feasible by both the TPS and the ray-tracing methods, but very sensitive to even small misalignments. In homogeneous regions, the range errors computed by the direct ray-tracing algorithm matched the results obtained by both the analytic and the Monte Carlo algorithms. In both phantoms, lateral heterogeneities were better modeled by the ray-tracing and the Monte Carlo algorithms than by the analytic TPS computation. Accordingly, when the pencil beam crossed lateral heterogeneities, the range errors mapped by the direct algorithm matched better the Monte Carlo maps than those obtained by the analytic algorithm. Finally, the simplicity of the ray-tracing algorithm allowed to implement a prototype procedure for automated spatial alignment. Conclusions: The ray-tracing algorithm can reliably replace the TPS method in MLIC PR for in vivo range verification and it can be a key component to develop software tools for spatial alignment and correction of CT calibration. (C) 2016 American Association of Physicists in Medicine