[Scientific assessment and regulatory approval of radiological screening examinations in Germany]. / Wissenschaftliche Bewertung und rechtliche Zulassung von radiologischen Früherkennungsuntersuchungen in Deutschland.

BACKGROUND: Radiologic imaging technologies like computed tomography (CT) have the potential to screen for various diseases. The potential benefits of screening are always associated with risks, particularly from the application of ionizing radiation. MATERIALS AND METHODS: The International Basic Safety Standards as well as the Council Directive 2013/59/Euratom have set guidelines for the application of ionizing radiation in early detection which were transposed into the German Radiation Protection Law. Accordingly, the German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) approves screening examinations on a generic level, based on a scientific report provided by the German Federal Office for Radiation Protection (BfS), and defines in a federal statutory ordinance which type of screening is permissible for detecting a disease for a particular group of persons and under which conditions. RESULTS: With exception of the mammography screening programme, no radiological examination for the early detection of disease has been approved in Germany to date. However, such screenings are currently being offered in Germany. The BfS is currently conducting a scientific evaluation for lung cancer screening with low-dose CT. CONCLUSIONS: Screening examinations with radiological imaging can only be approved when studies with the highest level of evidence have demonstrated that the benefits outweigh the risks. To translate this favourable benefit-risk balance into general health care, strict requirements for the entire screening process including quality assurance must be defined.

[Radiation protection in medical research : Licensing requirement for the use of radiation and advice for the application procedure]. / Strahlenschutz in der medizinischen Forschung : Genehmigungsbedürftigkeit von Strahlenanwendungen und Hinweise zum Antragsverfahren.

BACKGROUND: In Germany, persons who are to be exposed to radiation for medical research purposes are protected by a licensing requirement. However, there are considerable uncertainties on the part of the applicants as to whether licensing by the competent Federal Office for Radiation Protection is necessary, and regarding the choice of application procedure. AIM: The article provides explanatory notes and practical assistance for applicants and an outlook on the forthcoming new regulations concerning the law on radiation protection of persons in the field of medical research. MATERIALS AND METHODS: Questions and typical mistakes in the application process were identified and evaluated. RESULTS AND DISCUSSION: The qualified physicians involved in a study are responsible for deciding whether a license is required for the intended application of radiation. The decision can be guided by answering the key question whether the study participants would undergo the same exposures regarding type and extent if they had not taken part in the study. When physicians are still unsure about their decision, they can seek the advisory service provided by the professional medical societies. Certain groups of people are particularly protected through the prohibition or restriction of radiation exposure. A simplified licensing procedure is used for a proportion of diagnostic procedures involving radiation when all related requirements are met; otherwise, the regular licensing procedure should be used. The new radiation protection law, which will enter into force on the 31st of december 2018, provides a notification procedure in addition to deadlines for both the notification and the licensing procedures. In the article, the authors consider how eligible studies involving applications of radiation that are legally not admissible at present may be feasible in the future, while still ensuring a high protection level for study participants.

[Magnetic resonance imaging : Recent studies on biological effects of static magnetic and high­frequency electromagnetic fields]. / Magnetresonanztomographie : Neuere Studien zur biologischen Wirkung statischer Magnetfelder und hochfrequenter elektromagnetischer Felder.

PROBLEM: During the last few years, new studies on biological effects of strong static magnetic fields and on thermal effects of high-frequency electromagnetic fields used in magnetic resonance imaging (MRI) were published. Many of these studies have not yet been included in the current safety recommendations. METHOD: Scientific publications since 2010 on biological effects of static and electromagnetic fields in MRI were researched and evaluated. RESULTS: New studies confirm older publications that have already described effects of static magnetic fields on sensory organs and the central nervous system, accompanied by sensory perceptions. A new result is the direct effect of Lorentz forces on ionic currents in the semicircular canals of the vestibular system. Recent studies of thermal effects of high-frequency electromagnetic fields were focused on the development of anatomically realistic body models and a more precise simulation of exposure scenarios. RECOMMENDATION FOR PRACTICE: Strong static magnetic fields can cause unpleasant sensations, in particular, vertigo. In addition, they can influence the performance of the medical staff and thus potentially endanger the patient's safety. As a precaution, medical personnel should move slowly within the field gradient. High-frequency electromagnetic fields lead to an increase in the temperature of patients' tissues and organs. This should be considered especially in patients with restricted thermoregulation and in pregnant women and neonates; in these cases exposure should be kept as low as possible.

[Frequency and doses of diagnostic and interventional X­ray applications : Trends between 2007 and 2014]. / Häufigkeit und Dosis diagnostischer und interventioneller Röntgenanwendungen : Trends zwischen 2007 und 2014.

BACKGROUND: In Germany, approximately 95% of man-made radiation exposure of the population results from diagnostic and interventional X­ray procedures. Thus, radiation protection of patients in this field of application is of great importance. OBJECTIVE: Quantification and evaluation of current data on the frequency and doses of X­ray procedures as well as temporal trends for the years 2007-2014. MATERIAL AND METHODS: For outpatients the frequency of X­ray procedures was estimated using reimbursement data from health insurances and for inpatients by means of hospital statistics. For the years under review, representative values for the effective dose per X­ray application were determined mainly from data reported by X­ray departments to the competent authorities. RESULTS: In 2014 approximately 140 million X­ray procedures were performed in Germany with some 40% from dental examinations. On average 1.7 procedures per inhabitant and year were almost constantly carried out between 2007 and 2014. Besides dental diagnostics, X­ray examinations of the skeleton and thorax were performed most frequently. The number of computed tomography (CT) examinations increased by approximately 40%. The increase in magnetic resonance imaging (MRI) was even more pronounced with approximately 55% but overall CT examinations were still performed more often than MRI. The doses per X­ray procedure were only slightly reduced, despite the various dose reduction approaches established in recent years; therefore, the mean effective dose per inhabitant increased from approximately 1.4 mSv in 2007 to 1.6 mSv in 2014, mainly due to the increasing frequency of CT examinations. CONCLUSION: The principles of justification and optimization of radiological procedures are to be consistently applied in each individual instance, especially in the case of CT examinations.

Radiation exposure of patients undergoing whole-body FDG-PET/CT examinations: an update pursuant to the new ICRP recommendations.

AIM: Reinvestigation of the radiation exposure of patients undergoing whole-body [18F]FDG-PET/CT examinations pursuant to the revised recommendations of the ICRP. METHODS: Conversion coefficients for equivalent organ doses were determined for realistic anthropomorphic phantoms of reference persons. Based on these data, conversion coefficients for the effective dose were calculated using the revised tissue-weighting factors that account for the different radiation susceptibilities of organs and tissues, and the redefinition of the group 'remainder tissues'. RESULTS: Despite the markedly changed values of the equivalent organ doses estimated for FDG and of the tissue-weighting factors, the conversion coefficient for the effective dose resulting from FDG administration decreases only slightly by 10 %. For whole-body CT scans it remains even unchanged. CONCLUSION: The updated dose coefficients provide a valuable tool to easily assess the generic radiation risk of patients undergoing whole-body PET/CT (or PET/MRI) examinations and can be used, amongst others, for protocol optimization.

Whole-body CT for lymphoma staging: feasibility of halving radiation dose and risk by iterative image reconstruction.

OBJECTIVES: Patients with lymphoma are at higher-risk of secondary malignancies mainly due to effects of cancer therapy as well as frequent radiological surveillance. We thus aimed to investigate the objective and subjective image quality as well as radiation exposure and risk of full-dose standard (FDS), full-dose iterative (FDI), and half-dose iterative (HDI) image reconstruction in patients with lymphoma. MATERIAL AND METHODS: In 100 lymphoma patients, contrast-enhanced whole-body staging was performed on a dual-source CT. To acquire full-dose and half-dose CT data simultaneously, the total current-time product was equally distributed on both tubes operating at 120 kV. HDI reconstructions were calculated by using only data from one tube. Quantitative image quality was assessed by measuring image noise in different tissues of the neck, thorax, and abdomen. Overall diagnostic image quality was assessed using a 5-point Likert scale. Radiation doses and risks were estimated for a male and female reference person. RESULTS: For all anatomical regions apart from the lungs image noise was significantly lower and the overall subjective image quality significantly better when using FDI and HDI instead of FDS reconstruction (p<0.05). For the half-dose protocol, the risk to develop a radiation-induced cancer was estimated to be less than 0.11/0.19% for an adult male/female. CONCLUSIONS: Image quality of FDI and more importantly of HDI is superior to FDS reconstruction, thus enabling to halve radiation dose and risk to lymphoma patients.

Quantification of pulmonary microcirculation by dynamic contrast-enhanced magnetic resonance imaging: comparison of four regularization methods.

Tissue microcirculation can be quantified by a deconvolution analysis of concentration-time curves measured by dynamic contrast-enhanced magnetic resonance imaging. However, deconvolution is an ill-posed problem, which requires regularization of the solutions. In this work, four algebraic deconvolution/regularization methods were evaluated: truncated singular value decomposition and generalized Tikhonov regularization (GTR) in combination with the L-curve criterion, a modified LCC (GTR-MLCC), and a response function model that takes a-priori knowledge into account. To this end, dynamic contrast-enhanced magnetic resonance imaging data sets were simulated by an established physiologically reference model for different signal-to-noise ratios and measured on a 1.5-T system in the lung of 10 healthy volunteers and 20 patients. Analysis of both the simulated and measured dynamic contrast-enhanced magnetic resonance imaging datasets revealed that GTR in combination with the L-curve criterion does not yield reliable and clinically useful results. The three other deconvolution/regularization algorithms resulted in almost identical microcirculatory parameter estimates for signal-to-noise ratios > 10. At low signal-to-noise ratios levels (<10) typically occurring in pathological lung regions, GTR in combination with a modified L-curve criterion approximates the true response function much more accurately than truncated singular value decomposition and GTR in combination with response function model with a difference in accuracy of up to 76%. In conclusion, GTR in combination with a modified L-curve criterion is recommended for the deconvolution of dynamic contrast-enhanced magnetic resonance imaging curves measured in the lung parenchyma of patients with highly heterogeneous signal-to-noise ratios.

[Dynamic contrast-enhanced computed tomography. Tracer kinetics and radiation hygienic principles]. / Dynamische kontrastverstärkte Computertomographie. Tracerkinetische und strahlenhygienische Grundlagen.

Technical innovations in multislice computed tomography (CT) allow for larger volume coverage in ever shorter scan times. This progress has stimulated the clinical application of dynamic contrast-enhanced (DCE) CT techniques, which offer the possibility to noninvasively characterize tissue microcirculation in terms of well-defined physiological quantities. This educational review imparts to radiologists the essential physiological terms and definitions as well as the basic tracer kinetic concepts required for the analysis of DCE-CT data. In particular, four different approaches are presented and exemplified by the analysis of representative DCE data: the steepest-gradient method, model-free algebraic deconvolution in combination with the indicator-dilution theory, two-compartment modelling and the so-called adiabatic approximation to the homogeneity model. Even though DCE-CT offers substantial methodological and practical advantages as compared to DCE-MRI (magnetic resonance imaging), there are also two serious and interconnected shortcomings: the low contrast enhancement in relation to the noise level and the high exposure of patients to ionizing radiation. These limiting aspects are considered in detail from a radiation hygienic point of view, emphasizing the basic principles of justification and optimization. Clinically established as well as potential future applications of DCE-CT will be presented in a subsequent paper.

[Changes in the "medical research" licensing procedure under the German Radiation Protection Ordinance]. / Neuerungen im Genehmigungsverfahren "Medizinische Forschung" gemäß Röntgen- und Strahlenschutzverordnung.

This publication outlines the "medical research" licensing procedure as specified in the amendment of the German Radiation Protection Ordinance of November 1, 2011. The general licensing requirements for the use of radiation have not been changed by the amendment. Three so-called use restrictions (i. e., dose limits of 10 mSv and 20 mSv, age limit of 50 years) have been modified. They will only apply to healthy volunteers in the future. In addition, there are considerable simplifications with respect to applications and licensing procedures of the Federal Office for Radiation Protection (Bundesamt für Strahlenschutz, BfS) regarding the use of radiation in the newly introduced "accompanying diagnostics" ("Begleitdiagnostik") case group. The newly established, independent panel of experts at the German Radiological Society (Deutsche Röntgengesellschaft, DRG) may provide essential support to principal investigators, qualified physicians and sponsors for differentiating between "medical research" and "health care", the latter not being subject to licensing. An expert statement will be issued by the DRG within four weeks of an inquiry. This consulting service is subject to confidentiality, and is free of charge for inquirers and without any commitment.

Imaging of hypoxia using PET and MRI.

Tumor hypoxia is the result of an inadequate supply of oxygen to tumor cells which can be caused by multiple factors. It is associated with aggressive local tumor growth and invasion, increased risk of metastasis, higher resistance to radiotherapy (RT) and chemotherapy, overall resulting in a poor clinical prognosis. Many locally advanced solid tumors may exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumor mass. As hypoxia is a negative prognostic factor concerning response to radiotherapy and chemotherapy, in vivo measurement of tumor hypoxia could be helpful to identify patients with worse prognosis or patients that could benefit from appropriate treatments such as intensity modulated radiotherapy (IMRT) that may accurately conform the dose distribution to small intratumoral regions showing differences in the oxygen level. A manifold of different methods to assess the oxygen tension (pO2) in tissues have been developed, each of them offering advantages as well as drawbacks. They range from invasive direct measurement techniques of the pO2 in tissue by using a polarographic electrode, to non-invasive imaging techniques such as positron emission tomography (PET) or magnetic resonance imaging (MRI). This article provides an overview over the various methods, with a particular emphasis on PET and MRI for imaging of hypoxia, and reviews their performance in preclinical and clinical studies.

[Radiation hygiene in medical X-ray imaging. Part 3: radiation exposure of patients and risk assessment]. / Strahlenhygiene in der medizinischen Röntgenbildgebung : Teil 3: Strahlenexposition des Patienten und Risikobewertung.

The frequency of X-ray examinations in Germany and the resulting radiation exposure is amongst the highest in comparison with other European countries. To reduce medical radiation exposure and to safeguard radiation protection regulations, the X-ray ordinance stipulates a justification of each individual X-ray application. The justification principle means that the X-ray application should produce sufficient health benefit to offset the radiation risk. Such a benefit-risk assessment needs an adequate estimation of radiation risk. The aim of this paper is to explain the principles of benefit-risk assessment for different situations (e.g. healthcare and screening). The basics and concepts of radiation effects and radiation epidemiology as well as examples of risk estimation and benefit-risk assessments are given.

[Radiation hygiene in medical X-ray imaging: part 2: Assessment of radiation exposure and radiation protection measures]. / Strahlenhygiene in der medizinischen Röntgenbildgebung: Teil 2: Expositionsbestimmung und Strahlenschutzmaßnahmen.

In order to secure and continually improve radiation protection standards in the field of medical X-ray imaging, the German X-Ray Ordinance requires that each individual examination be properly justified and that any procedure undertaken be optimized. Diagnostic reference levels have been introduced in Germany as a measure of optimization for common and/or high-dose X-ray procedures, and are regularly checked for compliance by the competent Medical Experts Office. A prerequisite for the implementation of these regulatory requirements is the determination of readily measurable dose quantities. They also form the basis for the estimation of organ doses and of the effective dose for exposure and risk assessment. The aim of this paper is to describe the essential dosimetric concepts and methods used for the assessment of radiographic, fluoroscopic, and CT procedures. In addition, practical measures for reducing the radiation exposure of patients and personnel will be discussed.

[Radiation hygiene in medical X-ray imaging, part 1: physical and technical basics]. / Strahlenhygiene in der medizinischen Röntgenbildgebung, Teil 1 : Physikalisch-technische Grundlagen.

In this first part of a series of three articles on radiation hygiene in medical X-ray imaging the characteristics of X-rays, their interactions with matter and the components of X-ray equipment are described from a radiation protection point of view. The fundamental radiation protection measures like filtration and beam limitation are introduced as well as the various conventional and digital image receptor systems. Moreover the absorbed dose and other practical dose terms as well as metrological and theoretical methods for dose assessment are introduced. The aim of this paper is to explain the essential physical and technical basics of X-ray imaging and the assessment of the resulting radiation dose.

[Diagnostic reference levels for X-ray examinations: update 2010]. / Diagnostische Referenzwerte für Röntgenuntersuchungen: Aktualisierung 2010.

The diagnostic reference levels (DRLs) for diagnostic and interventional X-ray procedures established in 2003 were updated in July 2010 by the German Federal Office for Radiation Protection on the basis of mean patient doses in X-ray facilities surveyed by the so-called competent medical expert offices. The new DRLs are immediately in force and in most cases markedly below the respective old levels. Moreover DRLs for pediatric CT examinations have been newly introduced. This article briefly summarizes the concept of DRLs and the essential changes.

[Nuclear-medical irradiation during pregnancy. Risk assessment for the offspring]. / Nuklearmedizinische Strahlenexpositionen während der Schwangerschaft. Risikoabschätzungen für die Leibesfrucht.

UNLABELLED: AIM To estimate and evaluate the risks for the offspring due to the administration of radiopharmaceuticals to women during the first pregnancy weeks after conception (weeks p.c.). METHODS: The in-utero exposition of the embryo due to diagnostic nuclear medicine procedures, for which diagnostic reference levels (DRL) are specified, as well as due to radio iodine therapy (RIT) was determined. To this end, it is assumed that the activity of the diagnostic radiopharmaceuticals administered to the mother corresponds with the DRL and amounts to 600 MBq or 4 GBq 131I for RIT of benign or malignant thyroid disease, respectively. Based on these data, the radiation risk for the offspring was assessed and compared with the spontaneous risks (R0). RESULTS: The dose for the offspring does not exceed 7.8 mSv for the diagnostic procedures considered, resulting in an excess risk for the offspring of less than 0.12% (R0 approximately 25%) to die from cancer during life, of less than 0.07% (R0 approximately 0.2%) to develop cancer up to the age of 15 years, and of less than 0.16% (R0 approximately 2%) for hereditary effects. RIT during the first 8 weeks p.c. results in doses for the offspring of about 100-460 mSv, resulting in an excess risk for malformations of the child of 3.4%-22% (R0 approximately 6%). CONCLUSIONS: The risk of stochastic radiation effects for the offspring due to a diagnostic nuclear medicine procedure of the mother during the first 8 weeks p.c. is--compared with the spontaneous risks--very small; deterministic effects are unlikely. In contrast, deterministic effects for the offspring may occur following RIT. In order to decide on a possibly indicated abortion after RIT, an individual risk assessment is mandatory.

Dose reduction by automatic exposure control in multidetector computed tomography: comparison between measurement and calculation.

The aim of this study was to investigate the potential of dose reduction in multidetector computed tomography (MDCT) by current-modulated automatic exposure control (AEC) and to test the reliability of the dose estimation by the conventional CT dosimetry program CT-EXPO, when an average tube current is used. Phantom measurements were performed at a CT system with 64 detector rows for four representative examination protocols, each without and with current-modulated AEC. Organ and effective doses were measured by thermoluminescence dosimeters (TLD) at an anthropomorphic Alderson phantom and compared with those given by the calculation with CT-EXPO. The application of AEC yielded dose reductions between 27 and 40% (TLD measurements). While good linearity was observed between measured and computed effective dose values both without and with AEC, the organ doses showed large deviations between measurement and calculation. The dose to patients undergoing a MDCT examination can be reduced considerably by applying a current-modulated AEC. Dosimetric algorithms using a constant current-time product provide reliable estimates of the effective dose.

Contrast enhanced MRI and intravital fluorescence microscopy indicate improved tumor microcirculation in highly vascularized melanomas upon short-term anti-VEGFR treatment.

Anti-angiogenic therapy by blocking VEGF signalling combined with standard chemotherapy is a novel strategy for clinical cancer treatment. The mechanisms for enhanced antitumoral effects are still a matter of controversial debate. Tumor vessel "normalization" upon anti-angiogenic therapy leading to improved drug delivery has been proposed as possible mechanism. Therefore, aim of the study was to investigate tumor microvascular function upon anti-VEGFR treatment in highly vascularized melanomas. A detailed intravital-microscopic analysis of tumor microcirculation including the distribution pattern of vessel diameters and blood flow velocities was performed in melanomas grown in dorsal skinfold chambers of hamsters. Animals with highly vascularized established tumors were treated by a VEGFR tyrosin kinase inhibitor (SU5416) on 3 repetitive days. Tumor tissue oxygenation was measured by phosphorescence quenching technique. Overall tumor microcirculation of subcutaneous tumors was investigated by contrast enhanced MRI (CE-MRI). Vessel density was significantly decreased in treated animals. A significant shift in the distribution patterns towards increased vessel diameters and faster red blood cell velocities in remaining tumor vessels was observed upon anti-VEGF treatment, compensating reduced vascular density. Moreover, a trend towards elevated pO(2) levels in treated tumors was observed. Compared to controls, inflow kinetics of tumors quantified by CE-MRI as well as overall uptake of contrast agent in tumor tissue were significantly increased following short-term SU5416 treatment. In conclusion the results confirm temporarily improved tumor microvascular function in highly vascularized melanomas upon short term anti-VEGFR treatment leading to enhanced tumor blood supply and oxygenation potentially improving the efficacy of simultaneous chemo- or radiotherapy.

Cationic lipid complexed camptothecin (EndoTAG-2) improves antitumoral efficacy by tumor vascular targeting.

Neo-vascular targeting by cationic colloidal carriers enables to realize an innovative approach for tumor therapy. EndoTag-2 is a novel vascular targeting agent, comprising the mammalian topoisomerase I inhibitor camptothecin in its carboxylate form complexed to cationic lipid (cationic lipid complexed camptothecin). Here we studied tumor vascular targeting properties, antitumoral effects and mode of action of EndoTag-2. Tumor vascular targeting properties of fluorescently labelled EndoTag-2 were investigated by in vivo microscopy using A-MEL-3 tumors grown in the dorsal skinfold chamber preparation and by fluorescence histology of s.c. LLC-1 carcinomas. Therapeutic effects have been investigated in the s.c. LLC-1 carcinoma model and the L3.6pl human pancreatic cancer model implanted orthotopically in athymic nude mice. Antivascular effects have been studied by histological investigation of tumor microvessel density and non invasive investigation of tumor blood flow by dynamic contrast enhanced MRI imaging (DCE-MRI). EndoTag-2 selectively targeted tumor microvessels as confirmed by quantitative fluorescence microscopy. Compared to controls EndoTag-2 revealed remarkable antitumoral efficiency in s.c. LLC-1 carcinomas implanted in C57/Bl6 mice. Growth and metastasis of orthotopic L3.6pl human pancreatic tumors was significantly inhibited by EndoTag-2 treatment. Quantitative analysis of tumor microvessel density revealed significant reduction of microvessel density in lewis lung carcinomas up to 50%. DCE-MRI confirmed significant reduction of intratumoral vascular volume as well as tumor perfusion upon EndoTag-2 treatment. In conclusion this study shows that cationic lipid complexed camptothecin (EndoTag-2) is a markedly active antitumor agent based on an innovative vascular targeting approach.