Aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases such as tuberculosis or sarcoidosis and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. Here we show that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of Tsc2 was sufficient to induce hypertrophy and proliferation resulting in excessive granuloma formation in vivo. TSC2-deficient macrophages formed mTORC1-dependent granulomatous structures in vitro and showed constitutive proliferation mediated by the neo-expression of cyclin-dependent kinase 4 (CDK4). Moreover, mTORC1 promoted metabolic reprogramming via CDK4 towards increased glycolysis, while simultaneously inhibiting NF-κB signaling and apoptosis. Inhibition of mTORC1 induced apoptosis and completely resolved granulomas in myeloid TSC2-deficient mice. In human sarcoidosis patients mTORC1 activation, macrophage proliferation, and glycolysis were identified as hallmarks that correlated with clinical disease progression. Collectively, TSC2 maintains macrophage quiescence and prevents mTORC1-dependent granulomatous disease with clinical implications for sarcoidosis.

Recently, a new type of radiochromic film, the EBT-XD film, has been introduced for high dose radiotherapy. The EBT-XD film contains the same structure as the EBT3 film but has a slightly different composition and a thinner active layer. This study benchmarks the EBT-XD against EBT3 film for 6 MV and 10 MV photon beams, as well as for 97.4 MeV and 148.2 MeV proton beams and 15-100 kV x-rays. Dosimetric and film reading characteristics, such as post irradiation darkening, film orientation effect, lateral response artifact (LRA), film sensitivity, energy and beam quality dependency were investigated. Furthermore, quenching effects in the Bragg peak were investigated for a single proton beam energy for both film types, in addition measurements were performed in a spread-out Bragg peak. EBT-XD films showed the same characteristic on film darkening as EBT3. The effects between portrait and landscape orientation were reduced by 3.1% (in pixel value) for EBT-XD compared to EBT3 at a dose of 2000 cGy. The LRA is reduced for EBT-XD films for all investigated dose ranges. The sensitivity of EBT-XD films is superior to EBT3 for doses higher than 500 cGy. In addition, EBT-XD showed a similar dosimetric response for photon and proton irradiation with low energy and beam quality dependency. A quenching effect of 10% was found for both film types. The slight decrease in the thickness of the active layer and different composition configuration of EBT-XD resulted in a reduced film orientation effect and LRA, as well as a sensitivity increase in high-dose regions for both photon and proton beams. Overall, the EBT-XD film improved regarding film reading characteristics and showed advantages in the high-dose region for photon and proton beams.

Large area ionization chambers (LAICs) can be used to measure output factors of narrow beams. Dose area product measurements are proposed as an alternative to central-axis point dose measurements. Using such detectors requires detailed information on the uniformity of the response along the sensitive area. Eight LAICs were investigated in this study: four of type PTW-34070 (LAIC) and four of type PTW-34080 (LAIC). Measurements were performed in an x-ray unit using peak voltages of 100-200 kVp and a collimated beam of 3.1 mm (FWHM). The LAICs were moved with a step size of 5 mm to measure the chamber response at lateral positions. To account for beam positions where only a fraction of the beam impinged within the sensitive area of the LAICs, a corrected response was calculated which was the basis to calculate the relative response. The impact of a heterogeneous LAIC response, based on the obtained response maps was henceforth investigated for proton pencil beams and small field photon beams. A pronounced heterogeneity of the responses was observed in the investigated LAICs. The response of LAIC generally decreased with increasing radius, resulting in a response correction of up to 5%. This correction was more pronounced and more diverse (up to 10%) for LAIC. Considering a proton pencil beam the systematic offset for reference dosimetry was 2.4-4.1% for LAIC and  -9.5 to 9.4% for LAIC. For relative dosimetry (e.g. integral depth-dose curves) systematic response variation by 0.8-1.9% were found. For a decreasing photon field size the systematic offset for absolute dose measurements showed a 2.5-4.5% overestimation of the response for 6  ×  6 mm field sizes for LAIC. For LAIC the response varied even over a range of 20%. This study highlights the need for chamber-dependent response maps when using LAICs for absolute and relative dosimetry with proton pencil beams or small photon beams.

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Introduction: This paper explores the potential of the StyleGAN model as an high-resolution image generator for synthetic medical images. The possibility to generate sample patient images of different modalities can be helpful for training deep learning algorithms as e.g. a data augmentation technique. Methods: The StyleGAN model was trained on Computed Tomography (CT) and T2-weighted Magnetic Resonance (MR) images from 100 patients with pelvic malignancies. The resulting model was investigated with regards to three features: Image Modality, Sex, and Longitudinal Slice Position. Further, the style transfer feature of the StyleGAN was used to move images between the modalities. The root-mean-squard error (RMSE) and the Mean Absolute Error (MAE) were used to quantify errors for MR and CT, respectively. Results: We demonstrate how these features can be transformed by manipulating the latent style vectors, and attempt to quantify how the errors change as we move through the latent style space. The best results were achieved by using the style transfer feature of the StyleGAN (58.7 HU MAE for MR to CT and 0.339 RMSE for CT to MR). Slices below and above an initial central slice can be predicted with an error below 75 HU MAE and 0.3 RMSE within 4 cm for CT and MR, respectively. Discussion: The StyleGAN is a promising model to use for generating synthetic medical images for MR and CT modalities as well as for 3D volumes.

In-beam PET is a clinically proven method for monitoring ion beam cancer treatment. The objective is predominantly the verification of the range of the primary particles. Due to different processes leading to dose and activity, evaluation is done by comparing measured data to simulated. Up to now, the comparison is performed by well-trained observers (clinicians, physicists). This process is very time consuming and low in reproducibility. However, an automatic method is desirable. A one-dimensional algorithm for range comparison has been enhanced and extended to three dimensions. System-inherent uncertainties are handled by means of a statistical approach. To test the method, a set of data was prepared. Distributions of β(+)-activity calculated from treatment plans were compared to measurements performed in the framework of the German Heavy Ion Tumor Therapy Project at GSI Helmholtz Centre for Heavy Ion Research, Darmstadt, Germany. Artificial range deviations in the simulations served as test objects for the algorithm. Range modifications of different depth (4, 6 and 10 mm water equivalent path length) can be detected. Even though the sensitivity and specificity of a visual evaluation are higher, the method is feasible as the basis for the selection of patients from the data pool for retrospective evaluation of treatment and treatment plans and correlation with follow-up data. Furthermore, it can be used for the development of an assistance tool for a clinical application.

A novel breathing phantom was designed for being used in conventional and ion-beam radiotherapy as well as for medical imaging. Accurate dose delivery and patient safety are aimed to be verified for four-dimensional (4D) treatment techniques compensating for breathing-induced tumor motion. The phantom includes anthropomorphic components representing an average human thorax. It consists of real tissue equivalent materials to fulfill the requirements for dosimetric experiments and imaging purposes. The different parts of the torso (lungs, chest wall, and ribs) and the tumor can move independently. Simple regular movements, as well as more advanced patient-specific breathing cycles are feasible while a reproducible setup can be guaranteed. The phantom provides the flexibility to use different types of dosimetric devices and was designed in a way that it is robust, transportable and easy to handle. Tolerance levels and the reliability of the phantom setup were determined in combination with tests on motion accuracy and reproducibility by using infrared optical tracking technology. Different imaging was performed including positron emission tomography imaging, 4D computed tomography as well as real-time in-room imaging. The initial dosimetric benchmarking studies were performed in a photon beam where dose parameters are predictable and the dosimetric procedures well established.