Andreas Kjaer

Modelling and verification of relay interlocking systems

This paper describes how relay interlocking systems as used by the Danish railways can be formally modelled and verified. Such systems are documented by circuit diagrams describing their static layout. It is explained how to derive a state transition system model for the dynamic behaviour of a relay system from such diagrams. Safety properties are identified and formalised as LTL formulae. Model checking is finally used to verify that a model satisfies the safety properties. The method is tested for an existing station in Denmark.

Formal development of a tool for automated modelling and verification of relay interlocking systems

This paper describes a tool for formal modelling relay interlocking systems and explains how it has been stepwise, formally developed using the RAISE method. The developed tool takes the circuit diagrams of a relay interlocking system as input and gives as result a state transition system modelling the dynamic behaviour of the interlocking system, i.e. the dynamic behaviour of the circuits depicted in the diagrams. The resulting state transition system (model) is expressed in the SAL language such that the SAL model checker can be used to model check required properties of this model of the interlocking system. The tool has been applied to the circuit diagrams of Stenstrup station in Denmark and the resulting formal model has then been model checked to satisfy a number of required safety properties.

Angiogenesis PET Tracer Uptake (68Ga-NODAGA-E[(cRGDyK)]2) in Induced Myocardial Infarction in Minipigs

Angiogenesis is part of the healing process following an ischemic injury and is vital for the post-ischemic repair of the myocardium. Therefore, it is of particular interest to be able to noninvasively monitor angiogenesis. This might, not only permit risk stratification of patients following myocardial infarction, but could also facilitate development and improvement of new therapies directed towards stimulation of the angiogenic response. During angiogenesis endothelial cells must adhere to one another to form new microvessels. αvβ3 integrin has been found to be highly expressed in activated endothelial cells and has been identified as a critical modulator of angiogenesis. 68Ga-NODAGA-E[c(RGDyK)]2 (RGD) has recently been developed by us as an angiogenesis positron-emission-tomography (PET) ligand targeted towards αvβ3 integrin. In the present study, we induced myocardial infarction in Göttingen minipigs. Successful infarction was documented by 82Rubidium-dipyridamole stress PET and computed tomography. RGD uptake was demonstrated in the infarcted myocardium one week and one month after induction of infarction by RGD-PET. In conclusion, we demonstrated angiogenesis by noninvasive imaging using RGD-PET in minipigs hearts, which resemble human hearts. The perspectives are very intriguing and might permit the evaluation of new treatment strategies targeted towards increasing the angiogenetic response, e.g., stem-cell treatment.

An Uncommon Case of Pediatric Esthesioneuroblastoma Presenting as SIADH: 18F-FDG PET/CT in Staging and Post-Therapeutic Assessment

Esthesioneuroblastoma (ENB) is an uncommon neuroendocrine tumor originating from the olfactory neuroepithelium and accounts for 3–6% of all intranasal tumors [1]. ENBs can be locally aggressive and cause invasion and destruction of surrounding structures. Histological grading and clinical stage at presentation are highly predictive of survival and especially presence of lymph node and distant metastases are determining prognostic factors [2,3,4,5]. Thus, reliable imaging is essential in these patients. Conventional imaging modalities for staging ENB are magnetic resonance imaging (MRI) and computed tomography (CT). However, fluorine-18 fluoro-2-deoxy-d-glucose positron emission tomography/CT (18F-FDG PET/CT) has been reported as a valuable adjunct and was found to upstage 36% of ENB patients compared to conventional imaging [6]. We present a case demonstrating the diagnostic work-up and follow-up with 18F-FDG PET/CT in a young patient with ENB with a highly atypical clinical presentation.

Angiogenesis PET Tracer Uptake (68Ga-NODAGA-E[(cRGDyK)]2) in Induced Myocardial Infarction and Stromal Cell Treatment in Minipigs

Angiogenesis is considered integral to the reparative process after ischemic injury. The αvβ3 integrin is a critical modulator of angiogenesis and highly expressed in activated endothelial cells. 68Ga-NODAGA-E[(cRGDyK)]2 (RGD) is a positron-emission-tomography (PET) ligand targeted towards αvβ3 integrin. The aim was to present data for the uptake of RGD and correlate it with histology and to further illustrate the differences in angiogenesis due to porcine adipose-derived mesenchymal stromal cell (pASC) or saline treatment in minipigs after induction of myocardial infarction (MI). Three minipigs were treated with direct intra-myocardial injection of pASCs and two minipigs with saline. MI was confirmed by 82Rubidium (82Rb) dipyridamole stress PET. Mean Standardized Uptake Values (SUVmean) of RGD were higher in the infarct compared to non-infarct area one week and one month after MI in both pASC-treated (SUVmean: 1.23 vs. 0.88 and 1.02 vs. 0.86, p < 0.05 for both) and non-pASC-treated minipigs (SUVmean: 1.44 vs. 1.07 and 1.26 vs. 1.04, p < 0.05 for both). However, there was no difference in RGD uptake, ejection fractions, coronary flow reserves or capillary density in histology between the two groups. In summary, indications of angiogenesis were present in the infarcted myocardium. However, no differences between pASC-treated and non-pASC-treated minipigs could be demonstrated.

Abstract IA13: Real-time near-infrared fluorescence tracer imaging to guide sentinel node biopsy and tumor detection in head and neck cancer

Introduction: Near-infrared fluorescence (NIRF) imaging is an emerging technology with several important applications in oncologic surgery. Using fluorescent dyes and dedicated camera systems, real-time intraoperative imaging is provided to guide surgical procedures and allow for instant decision-making. NIRF imaging has the potential to improve the Sentinel Node Biopsy (SNB) procedure for staging of oral cavity cancer by facilitating intraoperative visual identification of the sentinel lymph node (SN). Also, NIRF imaging may be used in the search of head and neck unknown primaries (CUP) in combination with transoral robotic surgery (TORS). The feasibility of NIRF imaging for intraoperative SN detection was investigated in a series of oral cavity cancer patients. In addition, our initial experience of using NIRF imaging during TORS for detection of oropharyngeal cancer will also be reported (ongoing study). Methods: (1) A prospective study of patients with primary oral squamous cell carcinoma (OSCC) planned for tumor resection and SNB. Thirty patients were injected peritumorally with a bimodal tracer (ICG-99mTc-Nanocoll) followed by lymphoscintigraphy (LSG) and SPECT/CT to define the SNs and their anatomical location preoperatively. SNs were detected intraoperatively with a hand-held gamma-probe and a hand-held NIRF camera. (2) In a minor prospective series of patients with oropharyngeal cancer undergoing TORS Indocyanin Green (ICG) was systematically injected preoperatively. The aim was to guide primary tumor detection using the firefly NIRF modality incorporated in the Da Vinci Si robotic system. Results: (1) In the SNB study, 29 of 30 subjects (97%), all preoperatively defined SNs could be identified intraoperatively using a combination of radioactive and fluorescence guidance. Eleven of 94 SNs (12%) could only be identified in vivo using NIRF imaging and the majority of those were located in level 1 close to the primary tumor. (2) In the pilot ICG TORS study, the additional use of ICG for primary tumor identification was varying. Conclusions: Intraoperative NIRF imaging as a tool to guide cancer surgery seems promising and further exploration of this novel technology is warranted. A combined fluorescent and radioactive tracer for SNB is feasible and the additional use of NIRF imaging may improve the accuracy of SN identification in oral cancer patients. Intraoperative fluorescence guidance seems of particular value, when SNs are located in close proximity to the injection site. Combined TORS and NIRF imaging showed with a varying quality the localization of the oropharyngeal cancer. The combined procedure may have a potential role in the diagnostic algorithm in head and neck CUP patients facilitating the detection of the primary tumor. Citation Format: Christian von Buchwald, Anders Christensen, Niclas Rubek, Karina Juhl, Birgitte Charabi, Jann Mortensen, Katalin Kiss, Andreas Kjaer. Real-time near-infrared fluorescence tracer imaging to guide sentinel node biopsy and tumor detection in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA13.