Reliable treatment planning of highly conformal scanned ion beam therapy demands accurate tools for the determination and characterization of the individual pencil-like beams building up the integral dose delivery and related mixed radiation field. At present, clinically practicable inverse treatment planning systems (TPSs) can only rely on fast-performing analytical algorithms. However, the rapidly emerging though more computationally intensive Monte Carlo (MC) methods can be employed to complement analytical TPS, e.g., via accurate calculations of the input beam-model data, together with a considerable reduction of the measuring time. Here we present the work done for the application of the FLUKA MC code to support several aspects of scanned ion beam delivery and treatment planning at the Heidelberg Ion Beam Therapy Center (HIT). Emphasis is given to the generation of the accelerator library and of experimentally validated TPS input basic data which are now in clinical use for proton and carbon ion therapy. Additionally, MC dose calculations of planned treatments in water are shown to represent a valuable tool for supporting treatment plan verification in comparison to dosimetric measurements. This paper can thus provide useful information and guidelines for the start-up and clinical operation of forthcoming ion beam therapy facilities similar to HIT.

Our data indicate that BRAF gene mutations are a relatively common event in CC but not in HCC. Disruption of the Raf/MEK/ERK (MAPK) kinase pathway, either by RAS or BRAF mutation, was detected in approximately 62% of all CC and is therefore one of the most frequent defects in cholangiocellular carcinogenesis.

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Clinical investigations on post-irradiation PET/CT (positron emission tomography/computed tomography) imaging for in vivo verification of treatment delivery and, in particular, beam range in proton therapy are underway at Massachusetts General Hospital (MGH). Within this project, we have developed a Monte Carlo framework for CT-based calculation of dose and irradiation-induced positron emitter distributions. Initial proton beam information is provided by a separate Geant4 Monte Carlo simulation modelling the treatment head. Particle transport in the patient is performed in the CT voxel geometry using the FLUKA Monte Carlo code. The implementation uses a discrete number of different tissue types with composition and mean density deduced from the CT scan. Scaling factors are introduced to account for the continuous Hounsfield unit dependence of the mass density and of the relative stopping power ratio to water used by the treatment planning system (XiO (Computerized Medical Systems Inc.)). Resulting Monte Carlo dose distributions are generally found in good correspondence with calculations of the treatment planning program, except a few cases (e.g. in the presence of air/tissue interfaces). Whereas dose is computed using standard FLUKA utilities, positron emitter distributions are calculated by internally combining proton fluence with experimental and evaluated cross-sections yielding 11C, 15O, 14O, 13N, 38K and 30P. Simulated positron emitter distributions yield PET images in good agreement with measurements. In this paper, we describe in detail the specific implementation of the FLUKA calculation framework, which may be easily adapted to handle arbitrary phase spaces of proton beams delivered by other facilities or include more reaction channels based on additional cross-section data. Further, we demonstrate the effects of different acquisition time regimes (e.g., PET imaging during or after irradiation) on the intensity and spatial distribution of the irradiation-induced beta+-activity signal for the cases of head and neck and para-spinal tumour sites.

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The RAF/MEK/ERK (MAPK) signal transduction cascade is an important mediator of a number of cellular fates including growth, proliferation and survival. The BRAF gene, one of the human isoforms of RAF, is activated by oncogenic RAS, leading to cooperative effects in cells responding to growth factor signals. This study was performed to elucidate a possible function of BRAF in squamous cell carcinoma of the head and neck (HNSCC). Mutations of BRAF and KRAS2 were evaluated in 89 HNSCC and corresponding normal mucosa by direct DNA sequencing analyses after microdissection. The results obtained were correlated with histopathological variables. Activating BRAF missense mutations were identified in 3/89 HNSCC (3%). KRAS2 mutations were found in five out of 89 (6%) HNSCC examined. There were no mutations of KRAS2 and BRAF in non-neoplastic mucosa. We failed to observe a correlation between BRAF or KRAS2 mutations and histopathological factors. Our data indicate that BRAF gene mutations are relatively rare events in HNSCC. Although uncommon, BRAF mutations may identify a subset of patients with HNSCC sensitive to targeted therapy.

Monte Carlo (MC) simulations of beam interaction and transport in matter are increasingly considered as essential tools to support several aspects of radiation therapy. Despite the vast application of MC to photon therapy and scattered proton therapy, clinical experience in scanned ion beam therapy is still scarce. This is especially the case for ions heavier than protons, which pose additional issues like nuclear fragmentation and varying biological effectiveness. In this work, we present the evaluation of a dedicated framework which has been developed at the Heidelberg Ion Beam Therapy Center to provide automated FLUKA MC simulations of clinical patient treatments with scanned proton and carbon ion beams. Investigations on the number of transported primaries and the dimension of the geometry and scoring grids have been performed for a representative class of patient cases in order to provide recommendations on the simulation settings, showing that recommendations derived from the experience in proton therapy cannot be directly translated to the case of carbon ion beams. The MC results with the optimized settings have been compared to the calculations of the analytical treatment planning system (TPS), showing that regardless of the consistency of the two systems (in terms of beam model in water and range calculation in different materials) relevant differences can be found in dosimetric quantities and range, especially in the case of heterogeneous and deep seated treatment sites depending on the ion beam species and energies, homogeneity of the traversed tissue and size of the treated volume. The analysis of typical TPS speed-up approximations highlighted effects which deserve accurate treatment, in contrast to adequate beam model simplifications for scanned ion beam therapy. In terms of biological dose calculations, the investigation of the mixed field components in realistic anatomical situations confirmed the findings of previous groups so far reported only in homogenous water targets. This work can thus be useful to other centers commencing clinical experience in scanned ion beam therapy.

Sensitivity to visualize and detect prostate cancer improved using real-time elastography in addition to gray scale ultrasound during prostate biopsy. Overall sensitivity did not reach levels to omit a systematic biopsy approach.