Ordered Navigation on Multi-attributed Data Words

We study temporal logics and automata on multi-attributed data words. Recently, BD-LTL was introduced as a temporal logic on data words extending LTL by navigation along positions of single data values. As allowing for navigation wrt. tuples of data values renders the logic undecidable, we introduce ND-LTL, an extension of BD-LTL by a restricted form of tuple-navigation. While complete ND-LTL is still undecidable, the two natural fragments allowing for either future or past navigation along data values are shown to be Ackermann-hard, yet decidability is obtained by reduction to nested multi-counter systems. To this end, we introduce and study nested variants of data automata as an intermediate model simplifying the constructions. To complement these results we show that imposing the same restrictions on BD-LTL yields two 2ExpSpace-complete fragments while satisfiability for the full logic is known to be as hard as reachability in Petri nets

Analysis of glucocorticoid receptor function in murine lung development using cell type-specific gene ablation

A vast body of evidence from studies in humans as well as animals illustrates the pivotal role of glucocorticoid signalling during pre- and postnatal lung maturation. Consequently, corticosteroid treatment is the established standard regimen for pre-term infants and has served to reduce incidence and severity of the major complications, respiratory distress syndrome and bronchopulmonary dysplasia. Glucocorticoid effects are mediated by the glucocorticoid receptor (GR) which acts as a ligand-dependent transcription factor and controls target gene expression by DNA-binding-dependent as well as -independent mechanisms. In line with this, disruption of glucocorticoid signalling by germline inactivation of the GR gene in the mouse leads to respiratory failure and postnatal lethality. Intriguingly, mice carrying a point mutation which selectively impairs homodimeric binding of GR to its cognate response elements survive, indicating that the essential functions of GR during murine lung development are mediated via protein-protein interactions rather than DNA-binding. To further elucidate the modes of GR action which mediate these critical effects, conditional gene inactivation was employed taking advantage of the Cre/loxP recombination system. A series of mutant mice was generated, lacking GR in the mesenchyme, endothelial cells or the lung epithelium, respectively, allowing the assessment of the relative contribution of these compartments to the phenotype of the germline mutation. The beneficial effects of corticosteroids have commonly been attributed to their ability to induce the functional maturation of lung epithelial cells including the stimulation of surfactant synthesis as well as sodium and water transport across the epithelium. However, conditional inactivation of the GR gene in all epithelial cells of the developing lung did not impair survival. Although these mutant mice displayed a delayed progression through the late phases of lung maturation, this retardation did not affect respiratory function at birth and was compensated during the first days of life or an artificially prolonged pregnancy. In contrast, mice lacking GR specifically in mesenchymal cells displayed a morphogenetic phenotype strongly reminiscent of GR knockout animals and succumbed to death immediately after birth. Comparable to the germline mutants, lungs of mutant embryos did not proceed through the canalicular and saccular phases of pulmonary development but remained in the pseudoglandular stage until birth. At E18.5, they were characterized by cuboidal epithelial cells and an expansion of the mesenchymal compartment resulting in an almost complete lack of presumptive alveolar airspace. Mutant lungs showed an increased proliferation rate and failed to induce general differentiation markers such as p21cip1. Moreover, the mutation significantly altered the composition of the extracellular matrix which is known to be critical not only as a structural support but also for mesenchymal-epithelial interactions. Finally, endothelium-specific inactivation of the GR gene neither affected postnatal survival nor morphogenetic development of the lung precluding an important function of GR in endothelial cells during the development of the pulmonary vasculature. In summary, the present study demonstrates that GR in the developing murine lung epithelium is not essential for postnatal survival. Instead, critical glucocorticoid effects are mediated by GR action in the mesenchyme which is necessary to promote complete progression through the maturational phases of murine lung development. GR acts particularly in cells of the fibroblast lineage where it controls the composition of the extracellular matrix and is indispensible for the decrease in the general proliferation rate

Model-Checking Counting Temporal Logics on Flat Structures

We study several extensions of linear-time and computation-tree temporal logics with quantifiers that allow for counting how often certain properties hold. For most of these extensions, the model-checking problem is undecidable, but we show that decidability can be recovered by considering flat Kripke structures where each state belongs to at most one simple loop. Most decision procedures are based on results on (flat) counter systems where counters are used to implement the evaluation of counting operators

Evaluation of inter- and intrafractional motion of liver tumors using interstitial markers and implantable electromagnetic radiotransmitters in the context of image-guided radiotherapy (IGRT) – the ESMERALDA trial

Background: With the development of more conformal and precise radiation techniques such as Intensity-Modulated Radiotherapy (IMRT), Stereotactic Body Radiotherapy (SBRT) and Image-Guided Radiotherapy (IGRT), patients with hepatic tumors could be treated with high local doses by sparing normal liver tissue. However, frequently occurring large HCC tumors are still a dosimetric challenge in spite of modern high sophisticated RT modalities. This interventional clinical study has been set up to evaluate the value of different fiducial markers, and to use the modern imaging methods for further treatment optimization using physical and informatics approaches. Methods and design: Surgically implanted radioopaque or electromagnetic markers are used to detect tumor local-ization during radiotherapy. The required markers for targeting and observation during RT can be implanted in a previously defined optimal position during the oncologically indicated operation. If there is no indication for a surgical resection or open biopsy, markers may be inserted into the liver or tumor tissue by using ultrasound-guidance. Primary study aim is the detection of the patients´ anatomy at the time of RT by observation of the marker position during the indicated irradiation (IGRT). Secondary study aims comprise detection and recording of 3D liver and tumor motion during RT. Furthermore, the study will help to develop technical strategies and mechanisms based on the recorded information on organ motion to avoid inaccurate dose application resulting from fast organ motion and deformation. Discussion: This is an open monocentric non-randomized, prospective study for the evaluation of organ motion using interstitial markers or implantable radiotransmitter. The trial will evaluate the full potential of different fiducial markers to further optimize treatment of moving targets, with a special focus on liver lesions

Monitoring of patients treated with particle therapy using positron-emission-tomography (PET): the MIRANDA study

<p>Abstract</p> <p>Background</p> <p>The purpose of this clinical study is to investigate the clinical feasibility and effectiveness of offline Positron-Emission-Tomography (PET) quality assurance for promoting the accuracy of proton and carbon ion beam therapy.</p> <p>Methods/Design</p> <p>A total of 240 patients will be recruited, evenly sampled among different analysis groups including tumors of the brain, skull base, head and neck region, upper gastrointestinal tract including the liver, lower gastrointestinal tract, prostate and pelvic region. From the comparison of the measured activity with the planned dose and its corresponding simulated activity distribution, conclusions on the delivered treatment will be inferred and, in case of significant deviations, correction strategies will be elaborated.</p> <p>Discussion</p> <p>The investigated patients are expected to benefit from this study, since in case of detected deviations between planned and actual treatment delivery a proper intervention (e.g., correction) could be performed in a subsequent irradiation fraction. In this way, an overall better treatment could be achieved than without any in-vivo verification. Moreover, site-specific patient-population information on the precision of the ion range at HIT might enable improvement of the CT-range calibration curve as well as safe reduction of the treatment margins to promote enhanced treatment plan conformality and dose escalation for full clinical exploitation of the promises of ion beam therapy.</p> <p>Trial Registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01528670">NCT01528670</a></p

Long term results after fractionated stereotactic radiotherapy (FSRT) in patients with craniopharyngioma: maximal tumor control with minimal side effects

Purpose: There are already numerous reports about high local control rates in patients with craniopharyngioma but there are only few studies with follow up times of more than 10 years. This study is an analysis of long term control, tumor response and side effects after fractionated stereotactic radiotherapy (FSRT) for patients with craniopharyngioma. Patients and methods: 55 patients who were treated with FSRT for craniopharyngioma were analyzed. Median age was 37 years (range 6–70 years), among them eight children < 18 years. Radiotherapy (RT) was indicated for progressive disease after neurosurgical resection or postoperatively after repeated resection or partial resection. A median dose of 52.2 Gy (50 – 57.6 Gy) was applied with typical dose per fraction of 1.8 Gy five times per week. The regular follow up examinations comprised in addition to contrast enhanced MRI scans thorough physical examinations and clinical evaluation. Results: During median follow up of 128 months (2 – 276 months) local control rate was 95.3% after 5 years, 92.1% after 10 years and 88.1% after 20 years. Overall survival after 10 years was 83.3% and after 20 years 67.8% whereby none of the deaths were directly attributed to craniopharyngioma. Overall treatment was tolerated well with almost no severe acute or chronic side effects. One patient developed complete anosmia, another one’s initially impaired vision deteriorated further. In 83.6% of the cases with radiological follow up a regression of irradiated tumor residues was monitored, in 7 cases complete response was achieved. 44 patients presented themselves initially with endocrinologic dysfunction none of them showed signs of further deterioration during follow up. No secondary malignancies were observed. Conclusion: Long term results for patients with craniopharyngioma after stereotactic radiotherapy are with respect to low treatment related side effects as well as to local control and overall survival excellent

Comparison of intensity modulated radiotherapy (IMRT) with intensity modulated particle therapy (IMPT) using fixed beams or an ion gantry for the treatment of patients with skull base meningiomas

<p>Abstract</p> <p>Background</p> <p>To examine the potential improvement in treatment planning for patients with skull base meningioma using IMRT compared to carbon ion or proton beams with and without a gantry.</p> <p>Methods</p> <p>Five patients originally treated with photon IMRT were selected for the study. Ion beams were chosen using a horizontal beam or an ion gantry. Intensity controlled raster scanning and the intensity modulated particle therapy mode were used for plan optimization. The evaluation included analysis of dose-volume histograms of the target volumes and organs at risk.</p> <p>Results</p> <p>In comparison with carbon and proton beams only with horizontal beams, carbon ion treatment plans could spare the OARs more and concentrated on the target volumes more than proton and photon IMRT treatment plans. Using only a horizontal fixed beam, satisfactory plans could be achieved for skull base tumors.</p> <p>Conclusion</p> <p>The results of the case studies showed that using IMPT has the potential to overcome the lack of a gantry for skull base tumors. Carbon ion plans offered slightly better dose distributions than proton plans, but the differences were not clinically significant with established dose prescription concepts.</p

Optimization of carbon ion and proton treatment plans using the raster-scanning technique for patients with unresectable pancreatic cancer

Background: The aim of the thesis is to improve radiation plans of patients with locally advanced, unresectable pancreatic cancer by using carbon ion and proton beams. Patients and methods: Using the treatment planning system Syngo RT Planning (Siemens, Erlangen, Germany) a total of 50 treatment plans have been created for five patients with the dose schedule 15 × 3 Gy(RBE). With reference to the anatomy, five field configurations were considered to be relevant. The plans were analyzed with respect to dose distribution and individual anatomy, and compared using a customized index. Results: Within the index the three-field configurations yielded the best results, though with a high variety of score points (field setup 5, carbon ion: median 74 (range 48–101)). The maximum dose in the myelon is low (e.g. case 3, carbon ion: 21.5 Gy(RBE)). A single posterior field generally spares the organs at risk, but the maximum dose in the myelon is high (e.g. case 3, carbon ion: 32.9 Gy(RBE)). Two oblique posterior fields resulted in acceptable maximum doses in the myelon (e.g. case 3, carbon ion: 26.9 Gy(RBE)). The single-field configuration and the two oblique posterior fields had a small score dispersion (carbon ion: median 66 and 58 (range 62–72 and 40–69)). In cases with topographic proximity of the organs at risk to the target volume, the single-field configuration scored as well as the three-field configurations. Conclusion: In summary, the three-field configurations showed the best dose distributions. A single posterior field seems to be robust and beneficial in case of difficult topographical conditions and topographical proximity of organs at risk to the target volume. A setup with two oblique posterior fields is a reasonable compromise between three-field and single-field configurations

Adjuvant radiotherapy and chemoradiation with gemcitabine after R1 resection in patients with pancreatic adenocarcinoma

Background: The purpose of the study was to evaluate the effect of radiation therapy and chemoradiation with gemcitabine (GEM) after R1 resection in patients with pancreatic adenocarcinoma (PAC). Methods: We performed a retrospective analysis of 25 patients who were treated with postoperative radiotherapy (RT) or chemoradiation (CRT) after surgery with microscopically positive resection margins for primary pancreatic cancer (PAC). Median age was 60 years (range 34 to 74 years), and there were 17 male and 8 female patients. Fractionated RT was applied with a median dose of 49.6 Gy (range 36 to 54 Gy). Eight patients received additional intraoperative radiotherapy (IORT) with a median dose of 12 Gy. Results: Median overall survival (mOS) of all treated patients was 22 months (95% confidence interval (CI) 7.9 to 36.1 months) after date of resection and 21.1 months (95% CI 7.6 to 34.6 months) after start of (C)RT. Median progression-free survival (mPFS) was 13.0 months (95% CI 0.93 to 25 months). Grading (G2 vs. G3, P = 0.005) and gender (female vs. male, P = 0.01) were significantly correlated with OS. There was a significant difference in mPFS between male and female patients (P = 0.008). A total of 11 from 25 patients experienced local tumour progression, and 19 patients were diagnosed with either locoregional or distant failure. Conclusions: We demonstrated that GEM-based CRT can be applied in analogy to neoadjuvant protocols in the adjuvant setting for PAC patients at high risk for disease recurrence after incomplete resection. Patients undergoing additive CRT have a rather good OS and PFS compared to historical control patient groups

Clinical outcome after particle therapy for meningiomas of the skull base: toxicity and local control in patients treated with active rasterscanning

Background: Meningiomas of the skull base account for 25–30% of all meningiomas. Due to the complex structure of the cranial base and its close proximity to critical structures, surgery is often associated with substantial morbidity. Treatment options include observation, aggressive surgical intervention, stereotactic or conventional radiotherapy. In this analysis we evaluate the outcome of 110 patients with meningiomas of the skull base treated with particle therapy. It was performed within the framework of the “clinical research group heavy ion therapy” and supported by the German Research Council (DFG, KFO 214). Methods: Between May 2010 and November 2014, 110 Patients with skull base meningioma were treated with particle radiotherapy at the Heidelberg Ion Therapy Center (HIT). Primary localizations included the sphenoid wing (n = 42), petroclival region (n = 23), cavernous sinus (n = 4), sella (n = 10) and olfactory nerve (n = 4). Sixty meningiomas were benign (WHO °I); whereas 8 were high-risk (WHO °II (n = 7) and °III (n = 1)). In 42 cases histology was not examined, since no surgery was performed. Proton (n = 104) or carbon ion (n = 6) radiotherapy was applied at Heidelberg Ion Therapy Center (HIT) using raster-scanning technique for active beam delivery. Fifty one patients (46.4%) received radiotherapy due to tumor progression, 17 (15.5%) after surgical resection and 42 (38.2%) as primary treatment. Results: Median follow-up in this analysis was 46,8 months (95% CI 39,9–53,7; Q1-Q3 34,3–61,7). Particle radiotherapy could be performed safely without toxicity-related interruptions. No grade IV or V toxicities according to CTCAE v4.0 were observed. Particle RT offered excellent overall local control rates with 100% progression-free survival (PFS) after 36 months and 96.6% after 60 months. Median PFS was not reached due to the small number of events. Histology significantly impacted PFS with superior PFS after 5 years for low-risk tumors (96.6% vs. 75.0%, p = 0,02). Overall survival was 96.2% after 60 months and 92.0% after 72 months from therapy. Of six documented deaths, five were definitely not and the sixth probably not meningioma-related. Conclusion Particle radiotherapy is an excellent treatment option for patients with meningiomas of the skull base and can lead to long-term tumor control with minimal side effects. Other prospective studies with longer follow-up will be necessary to further confirm the role of particle radiotherapy in skull base meningioma