Toward semi-automatic biologically effective dose treatment plan optimisation for Gamma Knife radiosurgery

Objective. Dose-rate effects in Gamma Knife radiosurgery treatments can lead to varying biologically effective dose (BED) levels for the same physical dose. The non-convex BED model depends on the delivery sequence and creates a non-trivial treatment planning problem. We investigate the feasibility of employing inverse planning methods to generate treatment plans exhibiting desirable BED characteristics using the per iso-centre beam-on times and delivery sequence. Approach. We implement two dedicated optimisation algorithms. One approach relies on mixed-integer linear programming (MILP) using a purposely developed convex underestimator for the BED to mitigate local minima issues at the cost of computational complexity. The second approach (local optimisation) is faster and potentially usable in a clinical setting but more prone to local minima issues. It sequentially executes the beam-on time (quasi-Newton method) and sequence optimisation (local search algorithm). We investigate the trade-off between time to convergence and solution quality by evaluating the resulting treatment plans’ objective function values and clinical parameters. We also study the treatment time dependence of the initial and optimised plans using BED95 (BED delivered to 95% of the target volume) values. Main results. When optimising the beam-on times and delivery sequence, the local optimisation approach converges several orders of magnitude faster than the MILP approach (minutes versus hours-days) while typically reaching within 1.2% (0.02-2.08%) of the final objective function value. The quality parameters of the resulting treatment plans show no meaningful difference between the local and MILP optimisation approaches. The presented optimisation approaches remove the treatment time dependence observed in the original treatment plans, and the chosen objectives successfully promote more conformal treatments. Significance. We demonstrate the feasibility of using an inverse planning approach within a reasonable time frame to ensure BED-based objectives are achieved across varying treatment times and highlight the prospect of further improvements in treatment plan quality

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Investigation of dosimetric differences between the TMR 10 and convolution algorithm for Gamma Knife stereotactic radiosurgery

Since its inception, doses applied using Gamma Knife Radiosurgery (GKR) have been calculated using a simple TMR algorithm, which assumes the patient's head is of even density, the same as water. This results in a significant approximation of the dose delivered by the Gamma Knife. We investigated how GKR dose calculations varied when using a new convolution algorithm clinically available for GKR planning that takes into account density variations in the head compared with the established calculation algorithm. Fifty-five patients undergoing GKR and harboring 85 lesions were voluntarily and prospectively enrolled into the study. Their clinical treatment plans were created and delivered using TMR 10, but were then recalculated using the density correction algorithm. Dosimetric differences between the planning algorithms were noted. Beam on time (BOT), which is directly proportional to dose, was the main value investigated. Changes of mean and maximum dose to organs at risk (OAR) were also assessed. Phantom studies were performed to investigate the effect of frame and pin materials on dose calculation using the convolution algorithm. Convolution yielded a mean increase in BOT of 7.4% (3.6%–11.6%). However, approximately 1.5% of this amount was due to the head contour being derived from the CT scans, as opposed to measurements using the Skull Scaling Instrument with TMR. Dose to the cochlea calculated with the convolution algorithm was approximately 7% lower than with the TMR 10 algorithm. No significant difference in relative dose distribution was noted and CT artifact typically caused by the stereotactic frame, glue embolization material or different fixation pin materials did not systematically affect convolution isodoses. Nonetheless, substantial error was introduced to the convolution calculation in one target located exactly in the area of major CT artifact caused by a fixation pin. Inhomogeneity correction using the convolution algorithm results in a considerable, but consistent, dose shift compared to the TMR 10 algorithm traditionally used for GKR. A reduction of the prescription dose may be necessary to obtain the same clinical effect with the convolution algorithm. Head shape definition using CT outlining can reduce treatment uncertainty from head shape approximations

Establishment of a therapeutic ratio for Gamma Knife Radiosurgery of trigeminal neuralgia: The critical importance of biologically effective dose (BED) versus physical dose

International audienceObjectives: How variations of treatment time affect the safety/efficacy of Gamma Knife (GK) radiosurgery is a matter of considerable debate. Due to the relative simplicity of treatment planning for trigeminal neuralgia (TN) this question has been addressed in a group of these patients. Using the concept of biologically effective dose (BED) the effect of the two key variables, dose and treatment time have been taken into account.Methods: A retrospective analysis was carried out on 408 TN cases, treated between 1997 and 2010. Treatment involved the use of a single 4 mm iso-center. If conditions allowed, the iso-center was placed at a median distance of 7.5 mm from the emergence of the trigeminal nerve from the brain stem. Effects were assessed in terms of the incidence of the complication, hypoesthesia, or in terms of efficacy, the incidence of ‘pain free’ after 30 days and at 1 and 2 years. These responses were evaluated with respect to both the physical dose and the biological effective dose (BED), the latter using a bi-exponential repair model.Results: Re-evaluation showed that the prescription doses, at the 100% iso-dose, varied between 75 and 97.9 Gy, delivered over 25 - 135 min. The relationship between physical dose and the incidence of hypoesthesia was not significant; the overall incidence being approximately 20%. However, there was a clear relationship between BED and the incidence of hypoesthesia, the incidence increasing from < 5% after a BED of ∼1800 Gy2.47 to 42% after ∼2600 Gy2.47. Efficacy, in terms of freedom from pain, was approximately 90%, irrespective of the BED (1550-2600 Gy2.47) at 1 and 2 years. There was a suggestion from the data that ‘pain free’ status developed more slowly at lower BED values.Conclusion: These results strongly suggest that safety/efficacy may be better achieved by prescribing a specific BED instead of a physical dose. A dose/time to BED conversion table has been prepared to enable iso-BED prescriptions. This finding may dramatically change dose-planning strategies in the future. This concept needs to be validated in other indications where more complex dose-planning is required

Automatic Segmentation of Vestibular Schwannoma from T2-Weighted MRI by Deep Spatial Attention with Hardness-Weighted Loss

Automatic segmentation of vestibular schwannoma (VS) tumors from magnetic resonance imaging (MRI) would facilitate efficient and accurate volume measurement to guide patient management and improve clinical workflow. The accuracy and robustness is challenged by low contrast, small target region and low through-plane resolution. We introduce a 2.5D convolutional neural network (CNN) able to exploit the different in-plane and through-plane resolutions encountered in standard of care imaging protocols. We use an attention module to enable the CNN to focus on the small target and propose a supervision on the learning of attention maps for more accurate segmentation. Additionally, we propose a hardness-weighted Dice loss function that gives higher weights to harder voxels to boost the training of CNNs. Experiments with ablation studies on the VS tumor segmentation task show that: 1) the proposed 2.5D CNN outperforms its 2D and 3D counterparts, 2) our supervised attention mechanism outperforms unsupervised attention, 3) the voxel-level hardness-weighted Dice loss can improve the performance of CNNs. Our method achieved an average Dice score and ASSD of 0.87 and 0.43~mm respectively. This will facilitate patient management decisions in clinical practice.Comment: 9 pages, 4 figures, submitted to MICCA