New Technology and Techniques for Needle-Based Magnetic Resonance Image-Guided Prostate Focal Therapy

The most common diagnosis of prostate cancer is that of localized disease, and unfortunately the optimal type of treatment for these men is not yet certain. Magnetic resonance image (MRI)-guided focal laser ablation (FLA) therapy is a promising potential treatment option for select men with localized prostate cancer, and may result in fewer side effects than whole-gland therapies, while still achieving oncologic control. The objective of this thesis was to develop methods of accurately guiding needles to the prostate within the bore of a clinical MRI scanner for MRI-guided FLA therapy. To achieve this goal, a mechatronic needle guidance system was developed. The system enables precise targeting of prostate tumours through angulated trajectories and insertion of needles with the patient in the bore of a clinical MRI scanner. After confirming sufficient accuracy in phantoms, and good MRI-compatibility, the system was used to guide needles for MRI-guided FLA therapy in eight patients. Results from this case series demonstrated an improvement in needle guidance time and ease of needle delivery compared to conventional approaches. Methods of more reliable treatment planning were sought, leading to the development of a systematic treatment planning method, and Monte Carlo simulations of needle placement uncertainty. The result was an estimate of the maximum size of focal target that can be confidently ablated using the mechatronic needle guidance system, leading to better guidelines for patient eligibility. These results also quantified the benefit that could be gained with improved techniques for needle guidance

The origin and development of nonlymphoid tissue CD103+ DCs

CD103+ dendritic cells (DCs) in nonlymphoid tissues are specialized in the cross-presentation of cell-associated antigens. However, little is known about the mechanisms that regulate the development of these cells. We show that two populations of CD11c+MHCII+ cells separated on the basis of CD103 and CD11b expression coexist in most nonlymphoid tissues with the exception of the lamina propria. CD103+ DCs are related to lymphoid organ CD8+ DCs in that they are derived exclusively from pre-DCs under the control of fms-like tyrosine kinase 3 (Flt3) ligand, inhibitor of DNA protein 2 (Id2), and IFN regulatory protein 8 (IRF8). In contrast, lamina propria CD103+ DCs express CD11b and develop independently of Id2 and IRF8. The other population of CD11c+MHCII+ cells in tissues, which is CD103−CD11b+, is heterogenous and depends on both Flt3 and MCSF-R. Our results reveal that nonlymphoid tissue CD103+ DCs and lymphoid organ CD8+ DCs derive from the same precursor and follow a related differentiation program

Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

The effects of magnetic field distortion on the accuracy of passive device localization frames in MR imaging.

PURPOSE: The interventional magnetic resonance (MR) imaging environment presents many challenges for the accurate localization of interventional devices. In particular, geometric distortion of the static magnetic field may be both appreciable and unpredictable. This paper aims to quantify the sensitivity of localization error of various passive device localization frames to static magnetic field distortion in MR. METHODS: Three localization frames were considered based on having distinctly different methods of encoding position and orientation in MR images. For each frame, the effects of static field distortion were modeled, allowing rotational and translational errors to be computed as functions of the level of distortion, which was modeled using a first order approximation. Validation of the model was performed by imaging the localization frames in a 3T clinical MR scanner, and simulating the effects of static field distortion by varying the scanner\u27s center frequency and gradient shim values. RESULTS: Plots of the rotational and translational components of error in localization frame position and orientation estimates are provided for ranges of uniform static field distortions of 1-100 μT and static field distortion gradients of 0.01-1 mT/m in all three directions. The theoretical estimates are in good agreement with the results obtained by imaging. CONCLUSIONS: The error in position and orientation estimation of passive localization frames in MR can be sensitive to static magnetic field distortions. The level of sensitivity, the type of error (i.e., rotational or translational), and the direction of error are dependent on the frame\u27s design and the method used to image it. If 2D gradient echo imaging is employed, frames with position and orientation estimate sensitivity to slice-select error (such as the z-frame) should be avoided, since this source of error is not easily correctable. Accurate frame position and orientation estimates that are insensitive to static field distortion can be achieved using 2D gradient echo imaging if: (a) the method of determining position and orientation only uses in-plane measurements of marker positions, (b) the in-plane marker positions in images are not sensitive to slice-select error, and (c) methods of correcting in-plane error in the frequency-encoded direction are employed

Elastic registration of prostate MR images based on estimation of deformation states.

Magnetic resonance imaging (MRI) is being used increasingly for image-guided targeted biopsy and focal therapy of prostate cancer. In this paper, a combined rigid and deformable registration technique is proposed to register pre-treatment diagnostic 3T magnetic resonance (MR) images of the prostate, with the identified target tumor(s), to intra-treatment 1.5T MR images. The pre-treatment T2-weighted MR images were acquired with patients in a supine position using an endorectal coil in a 3T scanner, while the intra-treatment T2-weighted MR images were acquired in a 1.5T scanner before insertion of the needle with patients in the semi-lithotomy position. Both the rigid and deformable registration algorithms employ an intensity-based distance metric defined based on the modality independent neighborhood descriptors (MIND) between images. The optimization routine for estimating the rigid transformation parameters is initialized using four pairs of manually selected approximate corresponding points on the boundaries of the prostate. In this paper, the problem of deformable image registration is approached from the perspective of state estimation for dynamical systems. The registration algorithm employs a rather generic dynamic linear elastic model of the tissue deformation discretized by the finite element method (FEM). We use the model in a classical state estimation framework to estimate the deformation of the prostate based on the distance metric between pre- and intra-treatment images. Our deformable registration results using 17 sets of prostate MR images showed that the proposed method yielded a target registration error (TRE) of 1.87±0.94mm,2.03±0.94mm, and 1.70±0.93mm for the whole gland (WG), central gland (CG), and peripheral zone (PZ), respectively, using 76 manually-identified fiducial points. This was an improvement over the 2.67±1.31mm, 2.95±1.43mm, and 2.34±1.11mm, respectively for the WG, CG, and PZ after rigid registration alone. Dice similarity coefficients (DSC) in the WG, CG and PZ were 88.2±5.3, 85.6±7.6 and 68.7±6.9 percent, respectively. Furthermore, the mean absolute distances (MAD) between surfaces was 1.26±0.56mm and 1.27±0.55mm in the WG and CG, after deformable registration. These results indicate that the proposed registration technique has sufficient accuracy for localizing prostate tumors in MRI-guided targeted biopsy or focal therapy of clinically localized prostate cancer