A microscopic model of the dose distribution in hepatocellular carcinoma after selective internal radiation therapy.

The dosimetry evaluation for the selective internal radiation therapy is currently performed assuming a uniform activity distribution, which is in contrast with literature findings. A 2D microscopic model of the perfused liver was developed to evaluate the effect of two different 90Y microspheres distributions: i) homogeneous partitioning with the microspheres equally distributed in the perfused liver, and ii) tumor-clustered partitioning where the microspheres distribution is inferred from the patient specific images. METHODS: Two subjects diagnosed with liver cancer were included in this study. For each subject, abdominal CT scans acquired prior to the SIRT and post-treatment 90Y positron emission tomography were considered. Two microspheres partitionings were simulated namely homogeneous and tumor-clustered partitioning. The homogeneous and tumor-clustered partitionings were derived starting from CT images. The microspheres radiation is simulated by means of Russell's law. RESULTS: In homogenous simulations, the dose delivery is uniform in the whole liver while in the tumor-clustered simulations a heterogeneous distribution of the delivered dose is visible with higher values in the tumor regions. In addition, in the tumor-clustered simulation, the delivered dose is higher in the viable tumor than in the necrotic tumor, for all patients. In the tumor-clustered case, the dose delivered in the non-tumoral tissue (NTT) was considerably lower than in the perfused liver. CONCLUSIONS: The model proposed here represents a proof-of-concept for personalized dosimetry assessment based on preoperative CT images.

A Preclinical Validation of Iron Oxide Nanoparticles for Treatment of Perianal Fistulizing Crohn's Disease.

Fistulizing anoperineal lesions are severe complications of Crohn's disease (CD) that affect quality of life with a long-term risk of anal sphincter destruction, incontinence, permanent stoma, and anal cancer. Despite several surgical procedures, they relapse in about two-thirds of patients, mandating innovative treatments. Ultrasmall particles of iron oxide (USPIO) have been described to achieve in vivo rapid healing of deep wounds in the skin and liver of rats thanks to their nanobridging capability that could be adapted to fistula treatment. Our main purpose was to highlight preclinical data with USPIO for the treatment of perianal fistulizing CD. Twenty male Sprague Dawley rats with severe 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced proctitis were operated to generate two perianal fistulas per rat. At day 35, two inflammatory fistulas were obtained per rat and perineal magnetic resonance imaging (MRI) was performed. After a baseline MRI, a fistula tract was randomly drawn and topically treated either with saline or with USPIO for 1 min (n = 17 for each). The rats underwent a perineal MRI on postoperative days (POD) 1, 4, and 7 and were sacrificed for pathological examination. The primary outcome was the filling or closure of the fistula tract, including the external or internal openings. USPIO treatment allowed the closure and/or filling of all the treated fistulas from its application until POD 7 in comparison with the control fistulas (23%). The treatment with USPIO was safe, permanently closed the fistula along its entire length, including internal and external orifices, and paved new avenues for the treatment of perianal fistulizing Crohn's disease.

Radiosensitizing Fe-Au nanocapsules (hybridosomes®) increase survival of GL261 brain tumor-bearing mice treated by radiotherapy.

Glioblastoma remains a cancer for which the effectiveness of treatments has shown little improvement over the last decades. For this pathology, multiple therapies combining resection, chemotherapy and radiotherapy remain the norm. In this context, the use of high-Z nanoparticles such as gold or hafnium to potentiate radiotherapy is attracting more and more attention. Here, we evaluate the potentiating effect of hollow shells made of gold and iron oxide nanoparticles (hybridosomes®) on the radiotherapy of glioblastoma, using murine GL261-Luc+ brain tumor model. While iron oxide seems to have no beneficial effect for radiotherapy, we observe a real effect of gold nanoparticles-despite their low amount-with a median survival increase of almost 20% compared to radiotherapy only and even 33% compared to the control group. Cellular and in vivo studies show that a molecule of interest nano-precipitated in the core of the hybridosomes® is released and internalized by the surrounding brain cells. Finally, in vivo studies show that hybridosomes® injected intra-tumorally are still present in the vicinity of the brain tumor more than 5 days after injection (duration of the Stupp protocol's radiation treatment). Interestingly, one mouse treated with radiotherapy in the presence of gold-containing hybridosomes® survived 78 days. Monitoring of the tumoral growth of this long-term survivor using both MRI and bioluminescence revealed a decrease of the tumor size after treatment. These very encouraging results are a proof-of-concept that hybridosomes® are really effective tools for the development of combined therapies (chemo-radiotherapy).

Towards a patient-specific hepatic arterial modeling for microspheres distribution optimization in SIRT protocol.

Selective internal radiation therapy (SIRT) using Yttrium-90 loaded glass microspheres injected in the hepatic artery is an emerging, minimally invasive therapy of liver cancer. A personalized intervention can lead to high concentration dose in the tumor, while sparing the surrounding parenchyma. We propose a computational model for patient-specific simulation of entire hepatic arterial tree, based on liver, tumors, and arteries segmentation on patient's tomography. Segmentation of hepatic arteries down to a diameter of 0.5 mm is semi-automatically performed on 3D cone-beam CT angiography. The liver and tumors are extracted from CT-scan at portal phase by an active surface method. Once the images are registered through an automatic multimodal registration, extracted data are used to initialize a numerical model simulating liver vascular network. The model creates successive bifurcations from given principal vessels, observing Poiseuille's and matter conservation laws. Simulations provide a coherent reconstruction of global hepatic arterial tree until vessel diameter of 0.05 mm. Microspheres distribution under simple hypotheses is also quantified, depending on injection site. The patient-specific character of this model may allow a personalized numerical approximation of microspheres final distribution, opening the way to clinical optimization of catheter placement for tumor targeting.

Dynamic contrast-enhanced MRI: Study of inter-software accuracy and reproducibility using simulated and clinical data.

PURPOSE: To test the reproducibility and accuracy of pharmacokinetic parameter measurements on five analysis software packages (SPs) for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), using simulated and clinical data. MATERIALS AND METHODS: This retrospective study was Institutional Review Board-approved. Simulated tissues consisted of pixel clusters of calculated dynamic signal changes for combinations of Tofts model pharmacokinetic parameters (volume transfer constant [K(trans) ], extravascular extracellular volume fraction [ve ]), longitudinal relaxation time (T1 ). The clinical group comprised 27 patients treated for rectal cancer, with 36 3T DCE-MR scans performed between November 2012 and February 2014, including dual-flip-angle T1 mapping and a dynamic postcontrast T1 -weighted, 3D spoiled gradient-echo sequence. The clinical and simulated images were postprocessed with five SPs to measure K(trans) , ve , and the initial area under the gadolinium curve (iAUGC). Modified Bland-Altman analysis was conducted, intraclass correlation coefficients (ICCs) and within-subject coefficients of variation were calculated. RESULTS: Thirty-one examinations from 23 patients were of sufficient technical quality and postprocessed. Measurement errors were observed on the simulated data for all the pharmacokinetic parameters and SPs, with a bias ranging from -0.19 min(-1) to 0.09 min(-1) for K(trans) , -0.15 to 0.01 for ve , and -0.65 to 1.66 mmol.L(-1) .min for iAUGC. The ICC between SPs revealed moderate agreement for the simulated data (K(trans) : 0.50; ve : 0.67; iAUGC: 0.77) and very poor agreement for the clinical data (K(trans) : 0.10; ve : 0.16; iAUGC: 0.21). CONCLUSION: Significant errors were found in the calculated DCE-MRI pharmacokinetic parameters for the perfusion analysis SPs, resulting in poor inter-software reproducibility. J. Magn. Reson. Imaging 2016;43:1288-1300.

Characterizing the peritumoral brain zone in glioblastoma: a multidisciplinary analysis.

Glioblastoma (GB) is the most frequent and aggressive type of primary brain tumor. Recurrences are mostly located at the margin of the resection cavity in the peritumoral brain zone (PBZ). Although it is widely believed that infiltrative tumor cells in this zone are responsible for GB recurrence, few studies have examined this zone. In this study, we analyzed PBZ left after surgery with a variety of techniques including radiology, histopathology, flow cytometry, genomic, transcriptomic, proteomic, and primary cell cultures. The resulting PBZ profiles were compared with those of the GB tumor zone and normal brain samples to identify characteristics specific to the PBZ. We found that tumor cell infiltration detected by standard histological analysis was present in almost one third of PBZ taken from an area that was considered normal both on standard MRI and by the neurosurgeon under an operating microscope. The panel of techniques used in this study show that the PBZ, similar to the tumor zone itself, is characterized by substantial inter-patient heterogeneity, which makes it difficult to identify representative markers. Nevertheless, we identified specific alterations in the PBZ such as the presence of selected tumor clones and stromal cells with tumorigenic and angiogenic properties. The study of GB-PBZ is a growing field of interest and this region needs to be characterized further. This will facilitate the development of new, targeted therapies for patients with GB and the development of approaches to refine the per-operative evaluation of the PBZ to optimize the surgical resection of the tumor.

Preliminary MRI quality assessment and device acceptance guidelines for a multicenter bioclinical study: the GO Glioblastoma Project.

It is a major challenge to guarantee homogeneous acquisition during a prospective multicenter magnetic resonance imaging (MRI) study that makes use of different devices. The goal of the multicenter Grand Ouest Glioblastoma Project (GOGP) was to correlate MRI quantitative parameters with biological markers extracted from image-guided biopsies. Therefore, it was essential to ensure spatial coherence of the parameters as well as the signal intensity and homogeneity. The project included the same MRI protocol implemented on six devices from different manufacturers. The key point was the initial acceptance of the imaging devices and protocol sequences. For this purpose, and to allow comparison of quantitative patient data, we propose a specific method for quality assessment. A common quality control based on 10 parameters was established. Three pulse sequences of the clinical project protocol were applied using three test-objects. A fourth test-object was used to assess T1 accuracy. Although geometry-related parameters, signal-to-noise ratio, uniformity, and T1 measurements varied slightly depending on the different devices, they nevertheless remained within the recommendations and expectations of the multicenter project. This kind of quality control procedure should be undertaken as a prerequisite to any multicenter clinical project involving quantitative MRI and comparison of data acquisitions with quantitative biological image-guided biopsies.

Can dynamic contrast-enhanced magnetic resonance imaging combined with texture analysis differentiate malignant glioneuronal tumors from other glioblastoma?

An interesting approach has been proposed to differentiate malignant glioneuronal tumors (MGNTs) as a subclass of the WHO grade III and IV malignant gliomas. MGNT histologically resemble any WHO grade III or IV glioma but have a different biological behavior, presenting a survival twice longer as WHO glioblastomas and a lower occurrence of metastases. However, neurofilament protein immunostaining was required for identification of MGNT. Using two complementary methods, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and texture analysis (MRI-TA) from the same acquisition process, the challenge is to in vivo identify MGNT and demonstrate that MRI postprocessing could contribute to a better typing and grading of glioblastoma. Results are obtained on a preliminary group of 19 patients a posteriori selected for a blind investigation of DCE T1-weighted and TA at 1.5 T. The optimal classification (0/11 misclassified MGNT) is obtained by combining the two methods, DCE-MRI and MRI-TA.

MRI quantification of splenic iron concentration in mouse.

PURPOSE: To quantify hepatic and splenic iron load, which is a critical issue for iron overload disease diagnosis. MRI is useful to noninvasively determine liver iron concentration, but not proven to be adequate for robust evaluation of splenic iron load. We evaluated the usefulness of MRI-derived parameters to determine splenic iron concentration in mice. MATERIALS AND METHODS: A mouse model of experimental iron load was used. Multi-echo spin-echo images of liver and spleen were acquired at 4.7 Tesla. The parameters were tested at all echoes with and without an external reference. Splenic and hepatic iron concentrations were determined using biochemical assay as the gold standard. RESULTS: Our results show that (i) use of an internal or external reference is essential; (ii) optimal echo times were TE = 19.5 ms and TE = 32.5 ms for the liver and spleen, respectively; (iii) in the liver, the relationship between biochemical and MRI iron concentration determinations is logarithmic; (iv) in the spleen, the best relationship is an inverse function. CONCLUSION: A single spin-echo sequence allows robust estimation of hepatic and splenic iron content. Parameters classically used for hepatic iron concentration cannot be applied to splenic iron determination, which requires both the specific sequence and the adapted fitting function.

Coupling texture analysis and physiological modeling for liver dynamic MRI interpretation.

We coupled our physiological model of the liver, to a MRI simulator (SIMRI) in order to find image markers of the tumor growth. Some pathological modifications related to the development of Hepatocellular carcinoma are simulated (flows, permeability, vascular density). Corresponding images simulated at typical acquisition phases (arterial, portal) are compared to real images. The evolution of some textural features with arterial flow is also presented.

A physiologically based pharmacokinetic model of vascular-extravascular exchanges during liver carcinogenesis: application to MRI contrast agents.

The extraction of physiological parameters by non-invasive imaging techniques such as dynamic magnetic resonance imaging (MRI) or positron emission tomography requires a knowledge of molecular distribution and exchange between microvascularization and extravascular tissues. These phenomena not only depend on the physicochemical characteristics of the injected molecules but also the pathophysiological state of the targeted organ. We developed a five-compartment physiologically based pharmacokinetic model focused on hepatic carcinogenesis and MRI contrast agents. This model includes physical characteristics of the contrast agent, dual specific liver supply, microvessel wall properties and transport parameters that are compatible with hepatocarcinoma development. The evolution of concentrations in the five compartments showed significant differences in the distribution of three molecules (differentiated by their diameters and diffusion coefficients ranging, respectively, from 0.9 to 62 nm and from 68.10(-9) to 47.10(-7) cm(2) s(-1)) in simulated regeneration nodules and dysplastic nodules, as well as in medium- and poorly differentiated hepatocarcinoma. These results are in agreement with known vascular modifications such as arterialization that occur during hepatocarcinogenesis. This model can be used to study the pharmacokinetics of contrast agents and consequently to extract parameters that are characteristic of the tumor development (like permeability), after fitting simulated to in vivo data.

Magnetic resonance imaging contrast-enhanced relaxometry of breast tumors: an MRI multicenter investigation concerning 100 patients.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using extracellular contrast agents has proved to be useful for the characterization of breast tumors. DCE-MRI has demonstrated a high sensitivity (around 95%) but a rather poor and controversial specificity, varying, according to the different studies, from 45% to 90%. In order to increase (a) the specificity and (b) the robustness of this quantitative approach in multicenter evaluation (five MRI units), a quantitative approach called dynamic relaxometry has been developed. According to the proposed method, the time-dependent longitudinal relaxation rate measured on region of interest of the lesion was calculated during the contrast uptake, after intravenous bolus injection of contrast agent. A specifically developed method was used for fast R(1) measurements. Relaxometry time curves are fitted to the Tofts model allowing the measurement of the parameters describing the enhancement curve (maximum relation rate enhancement, initial, 30-s and 60-s slopes) and the tissue parameters [transfer constant (K(trans) min(-1)) and extracellular extravascular space fraction (v(e))]. Correspondence factorial analysis followed by hierarchical ascendant classification are then performed on the different parameters. Higher K(trans) values were observed in infiltrative ductal carcinomas than in infiltrative lobular carcinomas, in agreement with data published by other groups. Specificity of DCE-MRI has been increased up to 85%, with a sensitivity of 95% with K(trans)/v(e) and enhancement index I (ratio of initial slope by maximum relaxation rate enhancement). A multiparametric data analysis of the calculated parameters opens the way to include quantitative image-based information in new nosologic approaches to breast tumors.

Adoptive immunotherapy monitored by micro-MRI in experimental colorectal liver metastasis.

In this study we used the colon carcinoma DHDK12 cell line and generated single metastasis after subcapsular injection in BDIX rats as an experimental tumor model. The aim of the work was to set up in vitro experimental conditions to prepare immune effector cells and in vivo conditions for monitoring the effects of such cells injected as adoptive immunotherapy. Dendritic cells can process tumor cell antigens, induce a T-cell response and be used ex vivo to prepare activated lymphocytes. Lymphocytes were harvested from mesenteric lymph nodes and cocultured with bone marrow-derived autologous dendritic cells previously loaded with irradiated tumor cells. In vitro, the coculture: 1) induced the proliferation of lymphocytes, 2) expanded a preferential subpopulation of T CD8 lymphocytes, and 3) was in favor of lymphocyte cytotoxic activity against the DHDK12 tumor cell line. Activated lymphocytes were injected in the tumor-bearing rat portal vein. Parameters could be set to monitor tumor volume by micro MRI. This monitoring before and after treatment and immunohistochemical examinations revealed that: 1) micro MRI is an appropriate tool to survey metastasis growth in rat, 2) injected lymphocytes increase lesional infiltration with T CD8 cells even 15 days after treatment, 3) a dose of 50 millions lymphocytes is not sufficient to act on the course of the tumor.