Pulmonary magnetic resonance-guided online adaptive radiotherapy of locally advanced: the PUMA trial.

BACKGROUND: Patients with locally-advanced non-small-cell lung cancer (LA-NSCLC) are often ineligible for surgery, so that definitive chemoradiotherapy (CRT) represents the treatment of choice. Nevertheless, long-term tumor control is often not achieved. Intensification of radiotherapy (RT) to improve locoregional tumor control is limited by the detrimental effect of higher radiation exposure of thoracic organs-at-risk (OAR). This narrow therapeutic ratio may be expanded by exploiting the advantages of magnetic resonance (MR) linear accelerators, mainly the online adaptation of the treatment plan to the current anatomy based on daily acquired MR images. However, MR-guidance is both labor-intensive and increases treatment times, which raises the question of its clinical feasibility to treat LA-NSCLC. Therefore, the PUMA trial was designed as a prospective, multicenter phase I trial to demonstrate the clinical feasibility of MR-guided online adaptive RT in LA-NSCLC. METHODS: Thirty patients with LA-NSCLC in stage III A-C will be accrued at three German university hospitals to receive MR-guided online adaptive RT at two different MR-linac systems (MRIdian Linac®, View Ray Inc. and Elekta Unity®, Elekta AB) with concurrent chemotherapy. Conventionally fractioned RT with isotoxic dose escalation up to 70 Gy is applied. Online plan adaptation is performed once weekly or in case of major anatomical changes. Patients are followed-up by thoracic CT- and MR-imaging for 24 months after treatment. The primary endpoint is twofold: (1) successfully completed online adapted fractions, (2) on-table time. Main secondary endpoints include adaptation frequency, toxicity, local tumor control, progression-free and overall survival. DISCUSSION: PUMA aims to demonstrate the clinical feasibility of MR-guided online adaptive RT of LA-NSCLC. If successful, PUMA will be followed by a clinical phase II trial that further investigates the clinical benefits of this approach. Moreover, PUMA is part of a large multidisciplinary project to develop MR-guidance techniques. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05237453 .

Technical Note: On the feasibility of performing dosimetry in target and organ at risk using polymer dosimetry gel and thermoluminescence detectors in an anthropomorphic, deformable, and multimodal pelvis phantom.

OBJECTIVE: To assess the feasibility of performing dose measurements in the target (prostate) and an adjacent organ at risk (rectum) using polymer dosimetry gel and thermoluminescence detectors (TLDs) in an anthropomorphic, deformable, and multimodal pelvis phantom (ADAM PETer). METHODS: The 3D printed prostate organ surrogate of the ADAM PETer phantom was filled with polymer dosimetry gel. Nine TLD600 (LiF:Mg,Ti) were installed in 3 × 3 rows on a specifically designed 3D-printed TLD holder. The TLD holder was inserted into the rectum at the level of the prostate and fixed by a partially inflated endorectal balloon. Computed tomography (CT) images were taken and treatment planning was performed. A prescribed dose of 4.5 Gy was delivered to the planning target volume (PTV). The doses measured by the dosimetry gel in the prostate and the TLDs in the rectum ("measured dose") were compared to the doses calculated by the treatment planning system ("planned dose") on a voxel-by-voxel basis. RESULTS: In the prostate organ surrogate, the 3D-γ-index was 97.7% for the 3% dose difference and 3 mm distance to agreement criterium. In the center of the prostate organ surrogate, measured and planned doses showed only minor deviations (<0.1 Gy, corresponding to a percentage error of 2.22%). On the edges of the prostate, slight differences between planned and measured doses were detected with a maximum deviation of 0.24 Gy, corresponding to 5.3% of the prescribed dose. The difference between planned and measured doses in the TLDs was on average 0.08 Gy (range: 0.02-0.21 Gy), corresponding to 1.78% of the prescribed dose (range: 0.44%-4.67%). CONCLUSIONS: The present study demonstrates the feasibility of using polymer dosimetry gel and TLDs for 3D and 1D dose measurements in the prostate and the rectum organ surrogates in an anthropomorphic, deformable and multimodal phantom. The described methodology might offer new perspectives for end-to-end tests in image-guided adaptive radiotherapy workflows.

Solving problems is smart, preventing them is wise: Lessons learned from the 2nd International DKFZ Conference on Cancer Prevention.

The 2nd International DKFZ Conference on Cancer Prevention (CCP2020) organized by the German Cancer Research Center (DKFZ) was held as a virtual event on 17-18 September 2020. The event gathered experts on cancer prevention from around the world with the aim of generating a stimulating interchange of opinions between clinicians and basic researchers working in the field. The talks and posters of the conference fueled exciting discussions and debates about the state of the art of cancer prevention and provided a comprehensive outlook on the many aspects of the field. The program was divided into three main sessions, illustrating the most recent methodological approaches and interventions in primary, secondary and tertiary prevention, enriched by introductory lectures depicting the most relevant aspects of each session. The key concepts covered in this meeting were risk factors, early detection, improving life after cancer, cancer prevention in Europe and personalized prevention. The importance of the latter was expressly highlighted, many presentations emphasizing that in the era of personalized medicine, prevention also needs to be based on the unique genetic, epigenetic, social and behavioral characteristics of the individual to achieve maximal efficacy. In this article, we summarize the key messages emerging from each section, with particular attention on the most important challenges yet to be met in the field of cancer prevention.

Technical Note: ADAM PETer - An anthropomorphic, deformable and multimodality pelvis phantom with positron emission tomography extension for radiotherapy.

OBJECTIVE: To develop an anthropomorphic, deformable and multimodal pelvis phantom with positron emission tomography extension for radiotherapy (ADAM PETer). METHODS: The design of ADAM PETer was based on our previous pelvis phantom (ADAM) and extended for compatibility with PET and use in 3T magnetic resonance imaging (MRI). The formerly manually manufactured silicon organ surrogates were replaced by three-dimensional (3D) printed organ shells. Two intraprostatic lesions, four iliac lymph node metastases and two pelvic bone metastases were added to simulate prostate cancer as multifocal and metastatic disease. Radiological properties [computed tomography (CT) and 3T MRI] of cortical bone, bone marrow and adipose tissue were simulated by heavy gypsum, a mixture of Vaseline and K2 HPO4 and peanut oil, respectively. For soft tissues, agarose gels with varying concentrations of agarose, gadolinium (Gd) and sodium fluoride (NaF) were developed. The agarose gels were doped with patient-specific activity concentrations of a Fluorine-18 labelled compound and then filled into the 3D printed organ shells of prostate lesions, lymph node and bone metastases. The phantom was imaged at a dual energy CT and a 3T PET/MRI scanner. RESULTS: The compositions of the soft tissue surrogates are the following (given as mass fractions of agarose[w%]/NaF[w%]/Gd[w%]): Muscle (4/1/0.027), prostate (1.35/4.2/0.011), prostate lesions (2.25/4.2/0.0085), lymph node and bone metastases (1.4/4.2/0.025). In all imaging modalities, the phantom simulates human contrast. Intraprostatic lesions appear hypointense as compared to the surrounding normal prostate tissue in T2-weighted MRI. The PET signal of all tumors can be localized as focal spots at their respective site. Activity concentrations of 12.0 kBq/mL (prostate lesion), 12.4 kBq/mL (lymph nodes) and 39.5 kBq/mL (bone metastases) were measured. CONCLUSION: The ADAM PETer pelvis phantom can be used as multimodal, anthropomorphic model for CT, 3T-MRI and PET measurements. It will be central to simulate and optimize the technical workflow for the integration of PET/MRI-based radiation treatment planning of prostate cancer patients.

Machine Learning Algorithms for Early Detection of Bone Metastases in an Experimental Rat Model.

Machine learning (ML) algorithms permit the integration of different features into a model to perform classification or regression tasks with an accuracy exceeding its constituents. This protocol describes the development of an ML algorithm to predict the growth of breast cancer bone macrometastases in a rat model before any abnormalities are observable with standard imaging methods. Such an algorithm can facilitate the detection of early metastatic disease (i.e., micrometastasis) that is regularly missed during staging examinations. The applied metastasis model is site-specific, meaning that the rats develop metastases exclusively in their right hind leg. The model's tumor-take rate is 60%-80%, with macrometastases becoming visible in magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) in a subset of animals 30 days after induction, whereas a second subset of animals exhibit no tumor growth. Starting from image examinations acquired at an earlier time point, this protocol describes the extraction of features that indicate tissue vascularization detected by MRI, glucose metabolism by PET/CT, and the subsequent determination of the most relevant features for the prediction of macrometastatic disease. These features are then fed into a model-averaged neural network (avNNet) to classify the animals into one of two groups: one that will develop metastases and the other that will not develop any tumors. The protocol also describes the calculation of standard diagnostic parameters, such as overall accuracy, sensitivity, specificity, negative/positive predictive values, likelihood ratios, and the development of a receiver operating characteristic. An advantage of the proposed protocol is its flexibility, as it can be easily adapted to train a plethora of different ML algorithms with adjustable combinations of an unlimited number of features. Moreover, it can be used to analyze different problems in oncology, infection, and inflammation.

CT-based attenuation correction of whole-body radiotherapy treatment positioning devices in PET/MRI hybrid imaging.

OBJECTIVE: To implement computed tomography (CT)-based attenuation maps of radiotherapy (RT) positioning hardware and radiofrequency (RF) coils to enable hybrid positron emission tomography/magnetic resonance imaging (PET/MRI)-based RT treatment planning. MATERIALS AND METHODS: The RT positioning hardware consisted of a flat RT table overlay, coil holders for abdominal scans, coil holders for head and neck scans and an MRI compatible hip and leg immobilization device. CT images of each hardware element were acquired on a CT scanner. Based on the CT images, attenuation maps of the devices were created. Validation measurements were performed on a PET/MR scanner using a 68Ge phantom (48 MBq, 10 min scan time). Scans with each device in treatment position were performed. Then, reference scans containing only the phantom were taken. The scans were reconstructed online (at the PET/MRI scanner) and offline (via e7tools on a PC) using identical reconstruction parameters. Average reconstructed activity concentrations of the device and reference scans were compared. RESULTS: The device attenuation maps were successfully implemented. The RT positioning devices caused an average decrease of reconstructed PET activity concentration in the range between -8.3 ± 2.1% (mean ± SD) (head and neck coil holder with coils) to -1.0 ± 0.5% (abdominal coil holder). With attenuation correction taking into account RT hardware, these values were reduced to -2.0 ± 1.2% and -0.6 ± 0.5%, respectively. The results of the offline and online reconstructions were nearly identical, with a difference of up to 0.2%. CONCLUSION: The decrease in reconstructed activity concentration caused by the RT positioning devices is clinically relevant and can successfully be corrected using CT-based attenuation maps. Both the offline and online reconstruction methods are viable options.

RBE-weighted doses in target volumes of chordoma and chondrosarcoma patients treated with carbon ion radiotherapy: Comparison of local effect models I and IV.

BACKGROUND AND PURPOSE: To compare the relative biological effectiveness (RBE)-weighted dose distributions in the target volume of chordoma and chondrosarcoma patients when using two different versions of the local effect model (LEM I vs. IV) under identical conditions. MATERIALS AND METHODS: The patient collective included 59 patients treated with 20 fractions of carbon ion radiotherapy for chordoma and low-grade chondrosarcoma of the skull base at the Helmholtzzentrum für Schwerionenforschung (GSI) in 2002 and 2003. Prescribed doses to the planning target volume (PTV) were 60 (n = 49), 66 (n = 2) and 70 (n = 8) Gy (RBE). The original treatment plans that were initially biologically optimized with LEM I, were now recalculated using LEM IV based on the absorbed dose distributions. The resulting RBE-weighted dose distributions were quantitatively compared to assess the clinical impact of LEM IV relative to LEM I in the target volume. RESULTS: LEM IV predicts 20-30 Gy (RBE) increased maximum doses as compared to LEM I, while minimum doses are decreased by 2-5 Gy (RBE). Population-based mean and median doses deviated by less than 2 Gy (RBE) between both models. CONCLUSIONS: LEM I and LEM IV-based RBE-weighted doses in the target volume may be significantly different. Replacing the applied model in patient treatments may therefore lead to local over- or underdosages in the tumor. If LEM IV is to be tested clinically, comparisons of the RBE-weighted dose distributions of both models are required for the individual patients to assess whether the LEM IV-plan would also be acceptable and prescribed dose as well as clinical outcome data have to be carefully reassessed.

EGFL7 enhances surface expression of integrin α5ß1 to promote angiogenesis in malignant brain tumors.

Glioblastoma (GBM) is a typically lethal type of brain tumor with a median survival of 15 months postdiagnosis. This negative prognosis prompted the exploration of alternative treatment options. In particular, the reliance of GBM on angiogenesis triggered the development of anti-VEGF (vascular endothelial growth factor) blocking antibodies such as bevacizumab. Although its application in human GBM only increased progression-free periods but did not improve overall survival, physicians and researchers still utilize this treatment option due to the lack of adequate alternatives. In an attempt to improve the efficacy of anti-VEGF treatment, we explored the role of the egfl7 gene in malignant glioma. We found that the encoded extracellular matrix protein epidermal growth factor-like protein 7 (EGFL7) was secreted by glioma blood vessels but not glioma cells themselves, while no major role could be assigned to the parasitic miRNAs miR-126/126*. EGFL7 expression promoted glioma growth in experimental glioma models in vivo and stimulated tumor vascularization. Mechanistically, this was mediated by an upregulation of integrin α5ß1 on the cellular surface of endothelial cells, which enhanced fibronectin-induced angiogenic sprouting. Glioma blood vessels that formed in vivo were more mature as determined by pericyte and smooth muscle cell coverage. Furthermore, these vessels were less leaky as measured by magnetic resonance imaging of extravasating contrast agent. EGFL7-inhibition using a specific blocking antibody reduced the vascularization of experimental gliomas and increased the life span of treated animals, in particular in combination with anti-VEGF and the chemotherapeutic agent temozolomide. Data allow for the conclusion that this combinatorial regimen may serve as a novel treatment option for GBM.

A model of chronic enthesitis and new bone formation characterized by multimodal imaging.

Enthesitis is a key feature of several different rheumatic diseases. Its pathophysiology is only partially known due to the lack of access to human tissue and the shortage of reliable animal models for enthesitis. Here, we aimed to develop a model that mimics the effector phase of enthesitis and reliably leads to inflammation and new bone formation. Enthesitis was induced by local injection of monosodium urate (MSU) crystals into the metatarsal entheses of wild-type (WT) or oxidative-burst-deficient (Ncf1**) mice. Quantitative variables of inflammation (edema, swelling) and vascularization (tissue perfusion) were assessed by magnetic resonance imaging (MRI), bone-forming activity by [18F]-fluoride positron emission tomography (PET), and destruction of cortical bone and new bone formation by computed tomography (CT). Non-invasive imaging was validated by histochemical and histomorphometric analysis. While injection of MSU crystals into WT mice triggered transient mild enthesitis with no new bone formation, Ncf1** mice developed chronic enthesitis accompanied by massive enthesiophytes. In MRI, inflammation and blood flow in the entheses were chronically increased, while PET/CT showed osteoproliferation with enthesiophyte formation. Histochemical analyses showed chronic inflammation, increased vascularization, osteoclast differentiation and bone deposition in the affected entheseal sites. Herein we describe a fast and reliable effector model of chronic enthesitis, which is characterized by a combination of inflammation, vascularization and new bone formation. This model will help to disentangle the molecular pathways involved in the effector phase of enthesitis.

Characterization of the murine orthotopic adamantinomatous craniopharyngioma PDX model by MRI in correlation with histology.

PURPOSE: Adamantinomatous craniopharyngiomas (ACP) as benign sellar brain tumors are challenging to treat. In order to develop robust in vivo drug testing methodology, the murine orthotopic craniopharyngioma model (PDX) was characterized by magnetic resonance imaging (MRI) and histology in xenografts from three patients (ACP1-3). METHODS: In ACP PDX, multiparametric MRI was conducted to assess morphologic characteristics such as contrast-enhancing tumor volume (CETV) as well as functional parameters from dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI) including area-under-the-curve (AUC), peak enhancement (PE), time-to-peak (TTP) and apparent diffusion coefficient (ADC). These MRI parameters evaluated in 27 ACP PDX were correlated to histological features and percentage of vital tumor cell content. RESULTS: Qualitative analysis of MRI and histology from PDX revealed a similar phenotype as seen in patients, although the MRI appearance in mice resulted in a more solid tumor growth than in humans. CETV were significantly higher in ACP2 xenografts relative to ACP1 and ACP3 which correspond to respective average vitality of 41%, <10% and 26% determined histologically. Importantly, CETV prove tumor growth of ACP2 PDX as it significantly increases in longitudinal follow-up of 110 days. Furthermore, xenografts from ACP2 revealed a significantly higher AUC, PE and TTP in comparison to ACP3, and significantly increased ADC relative to ACP1 and ACP3 respectively. Overall, DCE-MRI and DWI can be used to distinguish vital from non-vital grafts, when using a cut off value of 15% for vital tumor cell content. CONCLUSIONS: MRI enables the assessment of craniopharyngioma PDX vitality in vivo as validated histologically.

Ultra-high field MRI of human hippocampi: Morphological and multiparametric differentiation of hippocampal sclerosis subtypes.

The aim of the present study is to differentiate subtypes of hippocampal sclerosis (HS) using ex vivo ultra-high field magnetic resonance imaging (MRI). Included were 14 surgically resected hippocampi of patients with medically intractable temporal lobe epilepsy. The resected hippocampi were histologically categorized into subtypes of hippocampal sclerosis (HS type 1 (n = 10), HS type 2 (n = 2) and no-HS (n = 2)) and subsequently scanned on a preclinical 7T MRI acquiring T2-weighted morphology, relaxometry and diffusion tensor imaging. On the morphological images, the pyramidal cell layer (PCL) of the hippocampus was segmented and the following parameters were derived: T2 signal intensity, T1-, T2- and T2*-relaxation times, apparent diffusion coefficient (ADC), fractional anisotropy (FA) and mean diffusivity (MD). Furthermore, the area of the PCL was determined, as well as the parameter product which refers to the widths of the PCL parallel and perpendicular to the stratum moleculare. Spearman correlation coefficient was used to demonstrate relationships between MR-parameters and type of sclerosis. In comparison to no-HS specimens, the PCL was significantly narrower in HS type 1 and HS type 2 hippocampi. This narrowing affected the entire cornu ammonis sector (CA) 1 in HS type 1, while it was limited to the upper half of CA1 in direction to CA2 in HS type 2. The parameter product median increased from 0.43 to 1.67 and 2.91 mm2 for HS type 1, HS type 2 and no-HS, respectively. Correlation coefficients were significant for the PCL parameters product (0.73), area (0.71), T2*-time (-0.67), FA (0.65) and ADC (0.55). Our initial results suggest that HS type 1, HS type 2 and no-HS subtypes can be distinguished from each other using ex vivo UHF MRI based on T2-weighted morphologic images and the assessment of the parameter product. Upon clinical translation, UHF-MRI may provide a promising technique for the preoperative differentiation of HS subtypes in patients.

Early Alterations in Operant Performance and Prominent Huntingtin Aggregation in a Congenic F344 Rat Line of the Classical CAGn51trunc Model of Huntington Disease.

The transgenic rat model of Huntington disease expressing a fragment of mutant HTT (tgHD rat) has been thoroughly characterized and reproduces hallmark symptoms of human adult-onset HD. Pursuing the optimization of this model for evaluation of translational therapeutic approaches, the F344 inbred rat strain was considered as advantageous genetic background for the expression of the HD transgenic construct. In the present study, a novel congenic line of the SPRDtgHD transgenic model of HD, carrying 51 CAG repeats, was generated on the F344 rat genetic background. To assess the behavioral phenotype, classical assays investigating motor function, emotion, and sensorimotor gating were applied, along with automated screening of metabolic and activity parameters as well as operant conditioning tasks. The neuropathological phenotype was analyzed by immunohistochemistry and ex vivo magnetic resonance imaging. F344tgHD rats displayed markedly reduced anxiety-like behavior in the social interaction test and elevated impulsivity traits already at 3 months of age. Neuropathologically, reduced striatal volume and pronounced aggregation of mutant huntingtin in several brain regions were detected at later disease stage. In conclusion, the congenic F344tgHD model reproduces key aspects of the human HD phenotype, substantiating its value for translational therapeutic approaches.

Dose-response curves for MRI-detected radiation-induced temporal lobe reactions in patients after proton and carbon ion therapy: Does the same RBE-weighted dose lead to the same biological effect?

PURPOSE: To derive the dose-response curve for temporal lobe reactions (TLRs) after proton therapy and to compare the resulting relative biological effectiveness (RBE)-weighted tolerance doses based on an RBE of 1.1 with published values for carbon ions, which were calculated by the two versions of the local effect model (LEM I or IV). METHODS AND MATERIALS: 62 patients treated with protons for skull base tumors were analyzed for TLRs using magnetic resonance imaging. Within the mean follow-up time of 38 months, TLRs were observed in six patients. Dose-response curves based on the RBE-weighted maximum dose, excluding the 1 cm3-volume with the highest dose, were derived and compared to previously published dose-response curves for carbon ions, which were obtained using LEM I or IV, respectively. RESULTS: The dose-response curves for protons and LEM I were found to be almost identical while the curve of LEM IV was shifted toward higher doses. The resulting tolerance doses at the 5% effect level were 68.2+2.7-5.6, 68.6+3.0-3.9 and 78.3+3.8-5.0 Gy (RBE), respectively. CONCLUSIONS: The RBE-weighted dose prescription for protons leads to the same RBE-weighted dose-response curve for TLR as the one for LEM I-based carbon ions, while LEM IV predicts clinically significant higher tolerance doses.

Tumor Blood Vessel Visualization.

Noninvasive multimodal imaging of tumor blood vessels allows the qualitative and quantitative assessment of morphological, functional, and molecular features of tumor angiogenesis longitudinally in a living organism. In this chapter we focus on the application of magnetic resonance imaging (MRI), computed tomography (CT), ultrasound (US), and positron emission tomography (PET) in tumor blood vessel visualization on the example of breast cancer bone metastasis in a nude rat model. Thereby, materials and methods are described that are needed to obtain complementary data on tumor vascularization from these imaging techniques.

Genomic EWSR1 Fusion Sequence as Highly Sensitive and Dynamic Plasma Tumor Marker in Ewing Sarcoma.

PURPOSE: The application of the tumor-specific genomic fusion sequence as noninvasive biomarker for therapy monitoring in Ewing sarcoma (EwS) has been evaluated. EXPERIMENTAL DESIGN: EwS xenograft mouse models were used to explore detectability in small plasma volumes and correlation of genomic EWSR1-FLI1 copy numbers with tumor burden. Furthermore, 234 blood samples from 20 EwS patients were analyzed before and during multimodal treatment. EWSR1 fusion sequence levels in patients' plasma were quantified using droplet digital PCR and compared with tumor volumes calculated from MRI or CT imaging studies. RESULTS: Kinetics of EWSR1 fusion sequence copy numbers in the plasma are correlated with changes of the tumor volume in patients with localized and metastatic disease. The majority of patients showed a fast reduction of cell-free tumor DNA (ctDNA) during initial chemotherapy. Recurrence of increasing ctDNA levels signalized relapse development. CONCLUSIONS: Genomic fusion sequences represent promising noninvasive biomarkers for improved therapy monitoring in EwS. Until now, response assessment is largely based on MRI and CT imaging, implying restrictions on closely repeated performance and limitations on the differentiation between vital tumor and reactive stromal tissue. Particularly in patients with prognostic unfavorable disseminated disease, ctDNA is a valuable addition for the assessment of therapy response. Clin Cancer Res; 22(17); 4356-65. ©2016 AACR.

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy.

Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with α-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic α-synuclein on the formation of myelin sheaths to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic α-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of α-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel α-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic α-synuclein. Additionally, benztropine restored the α-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the α-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.

Temporal lobe reactions after carbon ion radiation therapy: comparison of relative biological effectiveness-weighted tolerance doses predicted by local effect models I and IV.

PURPOSE: To compare the relative biological effectiveness (RBE)-weighted tolerance doses for temporal lobe reactions after carbon ion radiation therapy using 2 different versions of the local effect model (LEM I vs LEM IV) for the same patient collective under identical conditions. METHODS AND MATERIALS: In a previous study, 59 patients were investigated, of whom 10 experienced temporal lobe reactions (TLR) after carbon ion radiation therapy for low-grade skull-base chordoma and chondrosarcoma at Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany in 2002 and 2003. TLR were detected as visible contrast enhancements on T1-weighted MRI images within a median follow-up time of 2.5 years. Although the derived RBE-weighted temporal lobe doses were based on the clinically applied LEM I, we have now recalculated the RBE-weighted dose distributions using LEM IV and derived dose-response curves with Dmax,V-1 cm³ (the RBE-weighted maximum dose in the remaining temporal lobe volume, excluding the volume of 1 cm³ with the highest dose) as an independent dosimetric variable. The resulting RBE-weighted tolerance doses were compared with those of the previous study to assess the clinical impact of LEM IV relative to LEM I. RESULTS: The dose-response curve of LEM IV is shifted toward higher values compared to that of LEM I. The RBE-weighted tolerance dose for a 5% complication probability (TD5) increases from 68.8 ± 3.3 to 78.3 ± 4.3 Gy (RBE) for LEM IV as compared to LEM I. CONCLUSIONS: LEM IV predicts a clinically significant increase of the RBE-weighted tolerance doses for the temporal lobe as compared to the currently applied LEM I. The limited available photon data do not allow a final conclusion as to whether RBE predictions of LEM I or LEM IV better fit better clinical experience in photon therapy. The decision about a future clinical application of LEM IV therefore requires additional analysis of temporal lobe reactions in a comparable photon-treated collective using the same dosimetric variable as in the present study.

Ion range estimation by using dual energy computed tomography.

Inaccurate conversion of CT data to water-equivalent path length (WEPL) is one of the most important uncertainty sources in ion treatment planning. Dual energy CT (DECT) imaging might help to reduce CT number ambiguities with the additional information. In our study we scanned a series of materials (tissue substitutes, aluminum, PMMA, and other polymers) in the dual source scanner (Siemens Somatom Definition Flash). Based on the 80kVp/140SnkVp dual energy images, the electron densities ϱe and effective atomic numbers Zeff were calculated. We introduced a new lookup table that translates the ϱe to the WEPL. The WEPL residuals from the calibration were significantly reduced for the investigated tissue surrogates compared to the empirical Hounsfield-look-up table (single energy CT imaging) from (-1.0±1.8)% to (0.1±0.7)% and for non-tissue equivalent PMMA from -7.8% to -1.0%. To assess the benefit of the new DECT calibration, we conducted a treatment planning study for three different idealized cases based on tissue surrogates and PMMA. The DECT calibration yielded a significantly higher target coverage in tissue surrogates and phantom material (i.e. PMMA cylinder, mean target coverage improved from 62% to 98%). To verify the DECT calibration for real tissue, ion ranges through a frozen pig head were measured and compared to predictions calculated by the standard single energy CT calibration and the novel DECT calibration. By using this method, an improvement of ion range estimation from -2.1% water-equivalent thickness deviation (single energy CT) to 0.3% (DECT) was achieved. If one excludes raypaths located on the edge of the sample accompanied with high uncertainties, no significant difference could be observed.