Towards mid-position based Stereotactic Body Radiation Therapy using online magnetic resonance imaging guidance for central lung tumours

Background and purpose: Central lung tumours can be treated by magnetic resonance (MR)-guided radiotherapy. Complications might be reduced by decreasing the Planning Target Volume (PTV) using mid-position (midP)-based planning instead of Internal Target Volume (ITV)-based planning. In this study, we aimed to verify a method to automatically derive patient-specific PTV margins for midP-based planning, and show dosimetric robustness of midP-based planning for a 1.5T MR-linac. Materials and methods: Central(n = 12) and peripheral(n = 4) central lung tumour cases who received 8x7.5 Gy were included. A midP-image was reconstructed from ten phases of the 4D-Computed Tomography using deformable image registration. The Gross Tumor Volume (GTV) was delineated on the midP-image and the PTV margin was automatically calculated based on van Herk's margin recipe, treating the standard deviation of all Deformation Vector Fields, within the GTV, as random error component. Dosimetric robustness of midP-based planning for MR-linac using automatically derived margins was verified by 4D dose-accumulation. MidP-based plans were compared to ITV-based plans. Automatically derived margins were verified with manually derived margins. Results: The mean D95% target coverage in GTV + 2 mm was 59.9 Gy and 62.0 Gy for midP- and ITV-based central lung plans, respectively. The mean lung dose was significantly lower for midP-based treatment plans (difference:-0.3 Gy; p<0.042). Automatically derived margins agreed within one millimeter with manually derived margins. Conclusions: This retrospective study indicates that mid-position-based treatment plans for central lung Stereotactic Body Radiation Therapy yield lower OAR doses compared to ITV-based treatment plans on the MR-linac. Patient-specific GTV-to-PTV margins can be derived automatically and result in clinically acceptable target coverage

Stereotactic body radiotherapy of central lung tumours using a 1.5 T MR-linac: First clinical experiences

BACKGROUND: MRI-guidance may aid better discrimination between Organs at Risk (OARs) and target volumes in proximity of the mediastinum. We report the first clinical experiences with Stereotactic Body Radiotherapy (SBRT) of (ultra)central lung tumours on a 1.5 T MR-linac. MATERIALS AND METHODS: Patients with an (ultra)central lung tumour were selected for MR-linac based SBRT treatment. A T2-weighted 3D sequence MRI acquired during free breathing was used for daily plan adaption. Prior to each fraction, contours of Internal Target Volume (ITV) and OARs were deformably propagated and amended by a radiation oncologist. Inter-fractional changes in volumes and coverage of target volumes as well as doses in OARs were evaluated in offline and online treatment plans. RESULTS: Ten patients were treated and completed 60 Gy in 8 or 12 fractions. In total 104 fractions were delivered. The median time in the treatment room was 41 min with a median beam-on time of 8.9 min. No grade ≥3 acute toxicity was observed. In two patients, the ITV significantly decreased during treatment (58 % and 37 %, respectively) due to tumour shrinkage. In the other patients, 81 % of online ITVs were within ±15 % of the volume of fraction 1. Comparison with the pre-treatment plan showed that ITV coverage of the online plan was similar in 52 % and improved in 34 % of cases. Adaptation to meet OAR constraints, led to decreased ITV coverage in 14 %. CONCLUSIONS: We describe the workflow for MR-guided Radiotherapy and the feasibility of using 1.5 T MR-linac for SBRT of (ultra) central lung tumours

Structural Basis for Dual-Inhibition Mechanism of a Non-Classical Kazal-Type Serine Protease Inhibitor from Horseshoe Crab in Complex with Subtilisin

Serine proteases play a crucial role in host-pathogen interactions. In the innate immune system of invertebrates, multi-domain protease inhibitors are important for the regulation of host-pathogen interactions and antimicrobial activities. Serine protease inhibitors, 9.3-kDa CrSPI isoforms 1 and 2, have been identified from the hepatopancreas of the horseshoe crab, Carcinoscorpius rotundicauda. The CrSPIs were biochemically active, especially CrSPI-1, which potently inhibited subtilisin (Ki = 1.43 nM). CrSPI has been grouped with the non-classical Kazal-type inhibitors due to its unusual cysteine distribution. Here we report the crystal structure of CrSPI-1 in complex with subtilisin at 2.6 Å resolution and the results of biophysical interaction studies. The CrSPI-1 molecule has two domains arranged in an extended conformation. These two domains act as heads that independently interact with two separate subtilisin molecules, resulting in the inhibition of subtilisin activity at a ratio of 1:2 (inhibitor to protease). Each subtilisin molecule interacts with the reactive site loop from each domain of CrSPI-1 through a standard canonical binding mode and forms a single ternary complex. In addition, we propose the substrate preferences of each domain of CrSPI-1. Domain 2 is specific towards the bacterial protease subtilisin, while domain 1 is likely to interact with the host protease, Furin. Elucidation of the structure of the CrSPI-1: subtilisin (1∶2) ternary complex increases our understanding of host-pathogen interactions in the innate immune system at the molecular level and provides new strategies for immunomodulation

Utilisation des dispositifs à transfert de charges en traitement analogique du signal

Les dispositifs à transfert de charges (DTC) sont des dispositifs analogiques. Qu'ils soient analysés sous forme de ligne à retards ou de registre à décalage, ils constituent une mémoire analogique où sont stockés autant d'échantillons d'un signal, qu'ils comportent d'étages. Leur comportement est à caractériser autant par les concepts classiques analogiques : niveaux de signal et de bruit, distortion, bande passante ; que ceux caractéristiques des mémoires : durée de mémorisation et fréquence de sortie. La technologie de leur réalisation est entièrement compatible avec celle des circuits à transistors MOS. Les circuits que nous présentons, associent DTC et circuits périphériques analogiques. Les résultats obtenus sur cette génération de circuits peuvent se résumé à : . dynamique 60dB . distortion 1/100 . fréquence de transfert maximale 200KHz . bande passante 20KHz . impédance de sortie 10 KΩ. Ces circuits sont des véhicules de test, tant en ce qui concerne le fonctionnement analogique du UTC que de son association avec une circuiterie analogique MOS. A partir de ces résultats préliminaires, nous commençons l'analyse de l'impact de ces concepts de fonctionnement, sur ce que serait le calcul d'une transformée de Fourier, d'un produit de convolution, d'une fonction de corrélation au moyen de dispositifs entièrement intégrés mettant en oeuvre DTC et circuits périphériques à transistors MOS

Automatic PTV margin determination for midposition-based lung SBRT planning on the Unity MR-linac

Purpose or Objective For midposition (midpos) based dose planning, a patient-specific PTV margin is typically determined by measuring the peak-to-peak (p2p) motion of the GTV during the breathing cycle. Our goal is to develop a new method to determine the PTV margin automatically for lung SBRT midpos-planning on the Unity MR-linac (Elekta AB, Stockholm, SE). Robustness of the automatic, patient-specific margin expansion is demonstrated using 4D dose accumulation. Materials and Methods 18 patients with a lung tumor were selected who received 8x7.5Gy (60Gy) SBRT. All patients were scanned with a 10-phase 4D-CT, from which a midpos CT was reconstructed using in-house deformable image registration software. Subsequently, the midpos CT was deformably warped to each 4D-phase, resulting in 10 deformable vector fields (DVFs). The GTV was delineated on the midpos CT. The mean standard deviations (SDauto) in the GTV over the DVFs, in all directions (CC, AP, LR), were calculated. Next, SDauto was inserted as random error in the Van Herk margin recipe, resulting in an individualized PTV margin. Treatment plans were optimized following departmental guidelines for MR-linac lung SBRT using Monaco-v5.40.01 (Elekta AB). To validate SDauto, a manual rigid registration of the lesion in all 4D phases was performed relative to the end-exhale phase. Based on the nine resulting displacement vectors, SDman was calculated for the GTV for all directions. As additional plausibility check, the p2p motion was divided by 3 and used as (semi-)random error (SDp2p) in the Van Herk margin recipe following the clinically used rule-of-thumb. Dosimetric robustness of the automatically derived margins was investigated with 4D dose accumulation. To this end, the midpos plans were recalculated on each phase of the 4D-CT, then the dose was warped to the midpos CT using the energy-mass transfer dose mapping and accumulated. V60Gy[%] in the GTV and V57Gy[%] for an expanded GTV (GTV+2mm) (2 mm isotopic expansion to incorporate delineation uncertainty) was used to assess target coverage. Results The SDauto and the SDman / SDp2p agreed for 94%/94% (RL) , 100%/78% (AP), and 72% / 78% (CC) of all patients within 1 mm (Fig 1). The largest differences with SDauto were observed for the CC direction for SDman [range: - 4.6 mm/+0.9 mm] and for SDp2p [range: -2.8 mm/+1.7 mm], in which tumor motion was largest. The automatically derived margin differed from the p2p-based margin in three cases by -1 mm and in one case by +1 mm in CC direction. No differences in margin were observed in AP and RL direction. Average GTV coverage (V60Gy) for the 4D accumulated dose plans was 98.9% (SD: 3.1%, range: 87.8%-100%) and for the planned dose 99.5% (SD: 2.0 %, range: 90.9%-100%) (Fig 2). The average GTV+2mm coverage (V57Gy) was 98.6% (SD: 3.4%, range: 86.1%-100%). Conclusion Automatic, patient-specific PTV margins are feasible for midpos-based MR-linac lung SBRT planning, and result in clinically acceptable target coverag