Viscoelastometry for detecting oral anticoagulants.

BACKGROUND: Determination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was performed to investigate the impact of anticoagulants on the results of viscoelastometric assays using the ClotPro device. METHODS: This prospective, observational study was conducted in patients receiving dabigatran, factor Xa (FXa)-inhibitors, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (local ethics committee approval number: 17-525-4). Healthy volunteers served as controls. Viscoelastometric assays were performed, including the extrinsic test (EX-test), intrinsic test (IN-test) Russel's viper venom test (RVV-test), ecarin test (ECA-test), and the tissue plasminogen activator test (TPA-test). RESULTS: 70 patients and 10 healthy volunteers were recruited. Clotting time in the EX-test (CTEX-test) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CTIN-test was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CTRVV-test in comparison with controls (median 200, 207 and 289 vs 63 s, respectively; all p < 0.0005). Only dabigatran elicited a significant increase in CTECA-test compared to controls (median 307 vs 73 s; p < 0.0001). CTECA-test correlated strongly with dabigatran plasma concentration (measured by anti-IIa activity; r = 0.9970; p < 0.0001) and provided 100% sensitivity and 100% specificity for detecting dabigatran. Plasma concentrations (anti-XA activity) of FXa inhibitors correlated with CTRVV-test (r = 0.7998; p < 0.0001), and CTRVV-test provided 83% sensitivity and 64% specificity for detecting FXa inhibitors. CONCLUSIONS: In emergency situations, ClotPro viscoelastometric assessment of whole-blood samples may help towards determining the presence and type of anticoagulant class that a patient is taking. TRIAL REGISTRATION: German clinical trials database ID: DRKS00015302 .

In vitro study to assess the efficacy of CDK4/6 inhibitor Palbociclib (PD-0332991) for treating canine mammary tumours.

Therapy of canine mammary tumours (CMTs) with classical antitumour drugs is problematic, so better therapeutic options are needed. Palbociclib (PD-0332991) is an innovative and effective anticancer drug for the treatment of breast cancer in women. Palbociclib is an inhibitor of cyclin-dependent kinase 4 (CDK4) and CDK6, which are key regulators of the cell cycle machinery and thus cell proliferation. In the present in vitro study, we investigated whether Palbociclib also represents a candidate drug to combat CMT. For this purpose, the effect of Palbociclib was analysed in P114 and CF41 cells, two CMT cell lines with an endogenous CDK4/6 co-expression. Incubation of P114 and CF41 cells with Palbociclib resulted in a dose- and time-dependent loss of phosphorylated retinoblastoma protein (pRb), a classical CDK4/6 substrate within the cell cycle machinery. Moreover, treatment of CMT cells with Palbociclib-induced cell cycle arrest affected cell viability, prevented colony formation and impaired cell migration activity. Palbociclib also inhibited the growth of P114 and CF41 cell spheroids. Immunohistochemical analysis of canine patient samples revealed a consistent expression of CDK6 in different canine mammary carcinoma types, but an individual and tumour-specific expression pattern of phosphorylated pRb independent of the tumour grade. Together, our findings let us suggest that Palbociclib has antitumour effects on CMT cells and that canine patients may represent potential candidates for treatment with this CDK4/6 inhibitor.

In vivo dosimetry with alanine/electron spin resonance dosimetry to evaluate the urethra dose during high-dose-rate brachytherapy.

PURPOSE: To determine the dose of the urethra during Ir-192 high-dose-rate brachytherapy in 15 patients, a new detector form developed for in vivo measurements was used as described by Anton et al. 2009. METHODS AND MATERIALS: The detector consists of alanine powder with paraffin as binder which was filled in a shrinkable tube for measurements. The alanine strand so produced was inserted in the foley catheter during high-dose-rate brachytherapy of the prostate. The measured dose was compared with the dose calculated by the treatment planning system SWIFT for 15 patients. After 8 patients, a marker was introduced for better positioning of the alanine strand using transrectal ultrasound images. RESULTS: The measurements of the dose of the urethra agreed very well with the dose calculated by SWIFT within the estimated standard uncertainty of the method for 8 patients with a mean absolute deviation of 0.08 Gy. However, for the other 7 patients, a mean absolute deviation between delivered and measured dose of -5.13 Gy was seen. For these patients, the active volume of the alanine dosimeter could not properly be reconstructed on the ultrasound images. CONCLUSION: The method presented in this study is useful for quality control of irradiations in vivo. To reconstruct the active volume on the corresponding ultrasound images, the correct application of the alanine strand in the urethra is very important. This procedure needs a well-trained physician.

Feasibility study of entrance and exit dose measurements at the contra lateral breast with alanine/electron spin resonance dosimetry in volumetric modulated radiotherapy of breast cancer.

The Physikalisch-Technische Bundesanstalt has established a secondary standard measurement system for the dose to water, D W, based on alanine/ESR (Anton et al 2013 Phys. Med. Biol. 58 3259-82). The aim of this study was to test the established measurement system for the out-of-field measurements of inpatients with breast cancer. A set of five alanine pellets were affixed to the skin of each patient at the contra lateral breast beginning at the sternum and extending over the mammilla to the distal surface. During 28 fractions with 2.2 Gy per fraction, the accumulated dose was measured in four patients. A cone beam computer tomography (CBCT) scan was generated for setup purposes before every treatment. The reference CT dataset was registered rigidly and deformably to the CBCT dataset for 28 fractions. To take the actual alanine pellet position into account, the dose distribution was calculated for every fraction using the Acuros XB algorithm. The results of the ESR measurements were compared to the calculated doses. The maximum dose measured at the sternum was 19.9 Gy ± 0.4 Gy, decreasing to 6.8 Gy ± 0.2 Gy at the mammilla and 4.5 Gy ± 0.1 Gy at the distal surface of the contra lateral breast. The absolute differences between the calculated and measured doses ranged from -1.9 Gy to 0.9 Gy. No systematic error could be seen. It was possible to achieve a combined standard uncertainty of 1.63% for D W = 5 Gy for the measured dose. The alanine/ESR method is feasible for in vivo measurements.

Making the right software choice for clinically used equipment in radiation oncology.

The customer of a new system for clinical use in radiation oncology must consider many options in order to find the optimal combination of software tools. Many commercial systems are available and each system has a large number of technical features. However an appraisal of the technical capabilities, especially the options for clinical implementations, is hardly assessable at first view.The intention of this article was to generate an assessment of the necessary functionalities for high precision radiotherapy and their integration in ROKIS (Radiation oncology clinic information system) for future customers, especially with regard to clinical applicability. Therefore we analysed the clinically required software functionalities and divided them into three categories: minimal, enhanced and optimal requirements for high conformal radiation treatment.

In-vitro analysis of the microbicidal activity of 6 contact lens care solutions.

BACKGROUND: Contact lens-related infections are often associated with inadequate contact lens hygiene, and therefore, contact lens care products should be able to sufficiently minimise the amount of pathogens that are responsible for these infections. In 2001, the EN ISO 14729 was introduced to ensure adequate disinfection efficacy of contact lens care solutions, but this norm has recently been criticised. METHODS: In this study, six frequently used contact lens care solutions were retested according to the Stand Alone Test of the EN ISO 14729 (2001). The Stand Alone Test is a quantitative suspension test. In addition, the products were tested in a modified setting adding an organic load. The load was a mixture of human blood serum, lysozyme, and mucine, which resembles tear fluid. RESULTS: The criteria of the Stand Alone Test recommended in EN ISO 14729 were only met by Aosept Plus. This 3% hydrogen-peroxide-based contact lens care solution attained a reduction factor of > 5 log units for bacteria and > 4 for fungi in all cases. Two further contact lens care solutions, Blue Vision and Optifree Replenish, met the criteria of a reduction factor of > 3 log units for bacteria and > 1 log unit for fungi, but only in the presence of artificial tear fluid. The three remaining products did not exhibit adequate disinfecting efficacy, at least against one of the tested microorganisms. CONCLUSIONS: Through the observation that the artificial tear fluid used in this study influences the disinfecting efficacy of contact lens care solutions, especially that of multi-purpose solutions, in a different way than does albumin, mucine, or even the organic load suggested in EN ISO 14729, it becomes obvious that the test conditions in the EN ISO 14729 should be revised in order to create more realistic conditions, e.g., by using a more realistic artificial tear fluid. Furthermore, we suggest adapting the EN ISO 14729 to the European test hierarchy for chemical disinfectants and antiseptics, which consists of three test phases and also requests meeting stricter criteria in order to pass the test. Unless the test conditions guarantee a sufficient reduction of potential pathogens, the risk of contact lens-related microbial keratitis and other infections will remain for the users.

Irradiation with protons for the individualized treatment of patients with locally advanced rectal cancer: a planning study with clinical implications.

BACKGROUND AND PURPOSE: Ongoing clinical trials aim to improve local control and overall survival rates by intensification of therapy regimen for patients with locally advanced rectal cancer. It is well known that whenever treatment is intensified, risk of therapy-related toxicity rises. An irradiation with protons could possibly present an approach to solve this dilemma by lowering the exposure to the organs-at-risk (OAR) without compromising tumor response. MATERIAL AND METHODS: Twenty five consecutive patients were treated from 04/2009 to 5/2010. For all patients, four different treatment plans including protons, RapidArc, IMRT and 3D-conformal-technique were retrospectively calculated and analyzed according to dosimetric aspects. RESULTS: Detailed DVH-analyses revealed that protons clearly reduced the dose to the OAR and entire normal tissue when compared to other techniques. Furthermore, the conformity index was significantly better and target volumes were covered consistent with the ICRU guidelines. CONCLUSIONS: Planning results suggest that treatment with protons can improve the therapeutic tolerance for the irradiation of rectal cancer, particularly for patients scheduled for an irradiation with an intensified chemotherapy regimen and identified to be at high risk for acute therapy-related toxicity. However, clinical experiences and long-term observation are needed to assess tumor response and related toxicity rates.

Rotational IMRT techniques compared to fixed gantry IMRT and tomotherapy: multi-institutional planning study for head-and-neck cases.

BACKGROUND: Recent developments enable to deliver rotational IMRT with standard C-arm gantry based linear accelerators. This upcoming treatment technique was benchmarked in a multi-center treatment planning study against static gantry IMRT and rotational IMRT based on a ring gantry for a complex parotid gland sparing head-and-neck technique. METHODS: Treatment plans were created for 10 patients with head-and-neck tumours (oropharynx, hypopharynx, larynx) using the following treatment planning systems (TPS) for rotational IMRT: Monaco (ELEKTA VMAT solution), Eclipse (Varian RapidArc solution) and HiArt for the helical tomotherapy (Tomotherapy). Planning of static gantry IMRT was performed with KonRad, Pinnacle and Panther DAO based on step&shoot IMRT delivery and Eclipse for sliding window IMRT. The prescribed doses for the high dose PTVs were 65.1Gy or 60.9Gy and for the low dose PTVs 55.8Gy or 52.5Gy dependend on resection status. Plan evaluation was based on target coverage, conformity and homogeneity, DVHs of OARs and the volume of normal tissue receiving more than 5Gy (V5Gy). Additionally, the cumulative monitor units (MUs) and treatment times of the different technologies were compared. All evaluation parameters were averaged over all 10 patients for each technique and planning modality. RESULTS: Depending on IMRT technique and TPS, the mean CI values of all patients ranged from 1.17 to 2.82; and mean HI values varied from 0.05 to 0.10. The mean values of the median doses of the spared parotid were 26.5Gy for RapidArc and 23Gy for VMAT, 14.1Gy for Tomo. For fixed gantry techniques 21Gy was achieved for step&shoot+KonRad, 17.0Gy for step&shoot+Panther DAO, 23.3Gy for step&shoot+Pinnacle and 18.6Gy for sliding window.V5Gy values were lowest for the sliding window IMRT technique (3499 ccm) and largest for RapidArc (5480 ccm). The lowest mean MU value of 408 was achieved by Panther DAO, compared to 1140 for sliding window IMRT. CONCLUSIONS: All IMRT delivery technologies with their associated TPS provide plans with satisfying target coverage while at the same time respecting the defined OAR criteria. Sliding window IMRT, RapidArc and Tomo techniques resulted in better target dose homogeneity compared to VMAT and step&shoot IMRT. Rotational IMRT based on C-arm linacs and Tomotherapy seem to be advantageous with respect to OAR sparing and treatment delivery efficiency, at the cost of higher dose delivered to normal tissues. The overall treatment plan quality using Tomo seems to be better than the other TPS technology combinations.

Dose uncertainty in radiotherapy of patients with head and neck cancer measured by in vivo ESR/alanine dosimetry using a mouthpiece.

In order (i) to evaluate the dose uncertainty of the mouthpiece in daily use during intensity-modulated radiotherapy of patients with head and neck cancer, and (ii) to present a system for in vivo dosimetry of the oral mucosa, we equipped the mouthpiece with alanine dosimeter probes for in vivo dosimetry. The aim was to determine the dose uncertainty caused by the daily positioning of the mouthpiece during dynamic treatment techniques. During IMRT radiotherapy of patients with head and neck cancer, the doses accumulated next to the mucosa were measured in five patients and compared to the dose calculated by the treatment planning system. The comparison of the applied and measured dose for each measurement point showed in six of the eight alanine probe positions a good agreement within the given relative combined standard uncertainty of less than 4.5% for a accumulated dose of 30 Gy and less than 4.6% for an accumulated dose of 8 Gy, respectively. In two of the eight alanine probe positions the applied and measured doses differed by 7.7% and 8.2% from each other. The dominant contribution to the overall uncertainty for the in vivo measurements was the positioning of the dosimeter probes in the patient's body and their corresponding localization in the CT data as well as the inaccuracy of the available algorithm for dose distribution calculation at the low-density material/soft tissue interface between the mouthpiece and the mucosa. Regarding our results, we refrain from the use of a mouthpiece during dynamic treatments such as IMRT.

Two years experience with quality assurance protocol for patient related Rapid Arc treatment plan verification using a two dimensional ionization chamber array.

PURPOSE: To verify the dose distribution and number of monitor units (MU) for dynamic treatment techniques like volumetric modulated single arc radiation therapy-Rapid Arc-each patient treatment plan has to be verified prior to the first treatment. The purpose of this study was to develop a patient related treatment plan verification protocol using a two dimensional ionization chamber array (MatriXX, IBA, Schwarzenbruck, Germany). METHOD: Measurements were done to determine the dependence between response of 2D ionization chamber array, beam direction, and field size. Also the reproducibility of the measurements was checked. For the patient related verifications the original patient Rapid Arc treatment plan was projected on CT dataset of the MatriXX and the dose distribution was calculated. After irradiation of the Rapid Arc verification plans measured and calculated 2D dose distributions were compared using the gamma evaluation method implemented in the measuring software OmniPro (version 1.5, IBA, Schwarzenbruck, Germany). RESULTS: The dependence between response of 2D ionization chamber array, field size and beam direction has shown a passing rate of 99% for field sizes between 7 cm×7 cm and 24 cm×24 cm for measurements of single arc. For smaller and larger field sizes than 7 cm×7 cm and 24 cm×24 cm the passing rate was less than 99%. The reproducibility was within a passing rate of 99% and 100%. The accuracy of the whole process including the uncertainty of the measuring system, treatment planning system, linear accelerator and isocentric laser system in the treatment room was acceptable for treatment plan verification using gamma criteria of 3% and 3 mm, 2D global gamma index. CONCLUSION: It was possible to verify the 2D dose distribution and MU of Rapid Arc treatment plans using the MatriXX. The use of the MatriXX for Rapid Arc treatment plan verification in clinical routine is reasonable. The passing rate should be 99% than the verification protocol is able to detect clinically significant errors.

Single fraction radiosurgery using Rapid Arc for treatment of intracranial targets.

BACKGROUND: Stereotactic-Radio-Surgery (SRS) using Conformal-Arc-Therapy (CAT) is a well established irradiation technique for treatment of intracranial targets. Although small safety margins are required because of very high accuracy of patient positioning and exact online localisation, there are still disadvantages like long treatment time, high number of monitor units (MU) and covering of noncircular targets. This planning study analysed whether Rapid Arc (RA) with stereotactic localisation for single-fraction SRS can solve these problems. METHODS: Ten consecutive patients were treated with Linac-based SRS. Eight patients had one or more brain metastases. The other patients presented a symptomatic vestibularis schwannoma and an atypic meningioma. For all patients, two plans (CAT/RA) were calculated and analysed. RESULTS: Conformity was higher for RA with additional larger low-dose areas. Furthermore, RA reduced the number of MU and the treatment time for all patients. Dose to organs at risk were equal or slightly higher using RA in comparison to CAT. CONCLUSIONS: RA provides a new alternative for single-fraction SRS irradiation combining advantages of short treatment time with lower number of MU and better conformity in addition to accuracy of stereotactic localisation in selected cases with uncomplicated clinical realization.

Overestimation of low-dose radiation in intensity-modulated radiotherapy with sliding-window technique.

PURPOSE: To analyze different control-system limitations on the measured dose distributions in low-dose regions of simplified intensity fields with an electronic portal imaging device to ascertain the optimal settings for the control-system limitations in the planning system. MATERIAL AND METHODS: The authors created one field with an "optimal fluence" of intensity 1.0 (full dose) and one field with intensity 0.0 (no dose) in the central part of the field. The influence of different dose rates (DRs) and maximum leaf speeds (LS) on the calculated and measured dose and dose profiles were analyzed. RESULTS: Good agreement between calculated and measured dose in the case of a field of intensity 1.0 was found. For the field with intensity 0.0, the measured dose was 20-60% lower than the dose calculated by the "actual fluence". The results were found dependent on the DR and LS. CONCLUSION: The overestimation in regions of optimal intensity 0.0 by the planning system cannot be resolved by the user. Taking the measured dose in the region of desired intensity 1.0 and other technical limitations (like beam hold interrupts or spikes in the cross and longitudinal profiles) into consideration, the application of an LS of 2.5 cm/s and a DR of 500 MU/min is recommended in order to minimize radiation dose applied to organs at risk, which are located in regions of low intensity, like, for example, the spinal cord.

Radiotherapy of malignant gliomas: comparison of volumetric single arc technique (RapidArc), dynamic intensity-modulated technique and 3D conformal technique.

PURPOSE: The analysis was designed to identify the optimal radiation technique for patients with malignant glioma. METHODS: A volumetric-modulated radiation treatment technique (RapidArc), an IMRT technique and a 3D conformal technique were calculated on computed tomograms of 14 consecutive patients with malignant glioma. The treatment plans were compared with each other using dose-volume histograms. RESULTS: The 3D conformal technique showed a good PTV coverage, if PTV was distant to organs at risk (OAR). If PTV was nearby OAR, the 3D technique revealed a poor PTV coverage in contrast to both intensity-modulated techniques. The conventional IMRT technique showed a slightly better PTV coverage than RapidArc. The advantages of RapidArc were a shorter treatment time, less monitor units and a small V(107%). CONCLUSIONS: If PTV is distant to OAR, the use of 3D conformal technique is sufficient. Otherwise an intensity-modulated technique should be used. RapidArc was faster than conventional IMRT and should be preferred if PTV coverage is adequate.

The delineation of target volumes for radiotherapy of lung cancer patients.

PURPOSE: Differences in the delineation of the gross target volume (GTV) and planning target volume (PTV) in patients with non-small-cell lung cancer are considerable. The focus of this work is on the analysis of observer-related reasons while controlling for other variables. METHODS: In three consecutive patients, eighteen physicians from fourteen different departments delineated the GTV and PTV in CT-slices using a detailed instruction for target delineation. Differences in the volumes, the delineated anatomic lymph node compartments and differences in every delineated pixel of the contoured volumes in the CT-slices (pixel-by-pixel-analysis) were evaluated for different groups: ten radiation oncologists from ten departments (ROs), four haematologic oncologists and chest physicians from four departments (HOs) and five radiation oncologists from one department (RO1D). RESULTS: Agreement (overlap > or = 70% of the contoured pixels) for the GTV and PTV delineation was found in 16.3% and 23.7% (ROs), 30.4% and 38.6% (HOs) and 32.8% and 35.9% (RO1D), respectively. CONCLUSION: A large interobserver variability in the PTV and much more in the GTV delineation were observed in spite of a detailed instruction for delineation. The variability was smallest for group ROID where due to repeated discussions and uniform teaching a better agreement was achieved.

In vivo dosimetry in the urethra using alanine/ESR during (192)Ir HDR brachytherapy of prostate cancer--a phantom study.

A phantom study for dosimetry in the urethra using alanine/ESR during (192)Ir HDR brachytherapy of prostate cancer is presented. The measurement method of the secondary standard of the Physikalisch-Technische Bundesanstalt had to be slightly modified in order to be able to measure inside a Foley catheter. The absorbed dose to water response of the alanine dosimetry system to (192)Ir was determined with a reproducibility of 1.8% relative to (60)Co. The resulting uncertainty for measurements inside the urethra was estimated to be 3.6%, excluding the uncertainty of the dose rate constant Lambda. The applied dose calculated by a treatment planning system is compared to the measured dose for a small series of (192)Ir HDR irradiations in a gel phantom. The differences between the measured and applied dose are well within the limits of uncertainty. Therefore, the method is considered to be suitable for measurements in vivo.

An easy irradiation technique (partial half-beam) to reduce renal dose in radiotherapy of cervical cancer including paraaortic lymph nodes.

PURPOSE: : For radiation treatment of patients with cervical cancer and a high risk for paraaortic lymph node involvement, an easy three-dimensional (3-D) conformal irradiation technique (partial half-beam [PHB]) for protection of organs at risk, especially of renal tissue, was developed. PATIENTS AND METHODS: : In five consecutive female patients a computed tomography scan was performed. Dose-volume histograms of the renal tissue and other organs at risk were analyzed for PHB, three other 3-D conformal techniques, and an intensitymodulated radiotherapy (IMRT) technique. RESULTS: : The PHB technique reduced the renal volume and volumes of other organs at risk exposed to radiation doses when comparing all patients to the other 3-D conformal techniques. With use of the IMRT technique more renal tissue volume received very low radiation doses (

Impact of different leaf velocities and dose rates on the number of monitor units and the dose-volume-histograms using intensity modulated radiotherapy with sliding-window technique.

BACKGROUND: Intensity modulated radiotherapy (IMRT) using sliding window technique utilises a leaf sequencing algorithm, which takes some control system limitations like dose rates (DR) and velocity of the leafs (LV) into account. The effect of altering these limitations on the number of monitor units and radiation dose to the organs at risk (OAR) were analysed. METHODS: IMRT plans for different LVs from 1.0 cm/sec to 10.0 cm/sec and different DRs from 100 MU/min to 600 MU/min for two patients with prostate cancer and two patients with squamous cell cancer of the scalp (SCCscalp) were calculated using the same "optimal fluence map". For each field the number of monitor units, the dose volume histograms and the differences in the "actual fluence maps" of the fields were analysed. RESULTS: With increase of the DR and decrease of the LV the number of monitor units increased and consequentially the radiation dose given to the OAR. In particular the serial OARs of patients with SCCscalp, which are located outside the end position of the leafs and inside the open field, received an additional dose of a higher DR and lower LV is used. CONCLUSION: For best protection of organs at risk, a low DR and high LV should be applied. But the consequence of a low DR is both a long treatment time and also that a LV of higher than 3.0 cm/sec is mechanically not applicable. Our recommendation for an optimisation of the discussed parameters is a leaf velocity of 2.5 cm/sec and a dose rate of 300-400 MU/min (prostate cancer) and 100-200 MU/min (SCCscalp) for best protection of organs at risk, short treatment time and number of monitor units.

In vivo alanine/electron spin resonance (ESR) dosimetry in radiotherapy of prostate cancer: a feasibility study.

PURPOSE: We have developed a device to evaluate the potential of alanine/electron spin resonance (ESR) dosimetry for quality assurance in 3D conformal radiotherapy for prostate cancer. It consists of a rectal balloon carrying eight alanine dosimeter probes and two metal markers to document the exact position of the balloon. We measured the effects of an air-filled rectal balloon on the dose at the rectal wall and compared these results with the applied dose distribution of the treatment planning system. MATERIALS AND METHODS: During 10 fractions with 2.0 Gy per fraction, the accumulated doses were measured in 3 patients. The results of the ESR measurements were compared to the applied doses. RESULTS: It was possible to insert the device without clinical complications and without additional rectal discomfort for the patients. The measurements of the dose accumulated at the anterior and the posterior rectal wall agreed with the applied dose within a mean deviation of 1.5% (overestimation of the dose) and 3.5% (underestimation of the dose), respectively. However, clinically significant differences between applied and measured rectal doses were seen in a patient with a hip prosthesis. In this case, the dose at the anterior rectal wall was overestimated by the TPS by about 11% and the dose at the posterior rectal wall was underestimated by approximately 7%. CONCLUSION: The method presented in this study is useful for quality control of irradiations in vivo.

Microdetermination of fatty acids by gas chromatography and cardiovascular risk stratification by the "EPA+DHA level".

The therapeutic options for interfering with the electrical instability of a pathologically remodeled or ischaemic heart remain limited. Of increasing importance become interventions which target the fatty acid composition of blood and membrane lipids. In particular, the long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) provide parameters for stratification of risks associated with severe arrhythmia disorders and sudden cardiac death. Since EPA and DHA appear to have their anti-arrhythmogenic actions when present as free fatty acids, the parameters which determine a critical free fatty acid concentration are of great interest. In the present study, conclusions on EPA and DHA incorporation in blood lipids are derived from the administration of Omacor which contains highly purified (84%) EPA and DHA ethyl esters and reduced the risk of sudden cardiac death by 45% in post-myocardial infarction patients (GISSI-Prevention study). The "EPA+DHA level" is described as risk identifying parameter for severe arrhythmia disorders, particularly if they are associated with myocardial ischaemia. It appears essential not only to build up body stores for release of EPA and DHA but to provide also a sustained uptake of EPA and DHA in the form of ethyl esters. In contrast to more rapidly absorbed triacylglycerols from fish, ethyl esters are taken up slowly within 24 h. For the administration of 1 g/day Omacor to healthy volunteers, it is shown that in whole blood EPA is increased from 0.6% to 1.4% within 10 days while DHA is increased from 2.9% to 4.3%. After withdrawal, the EPA and DHA levels approach baseline values within 10 days. A gas chromatographic procedure was established which requires only 10 microl of whole blood for the identification of more than 30 fatty acids. Evidence is summarized strengthening the concept that a low "EPA+DHA level" presents a risk for severe arrhythmia disorders and sudden cardiac death. The administration of 840 mg/day of EPA and DHA ethyl esters raises the "EPA+DHA level" to approximately 6% that is associated with protection from sudden cardiac death. The pharmacological effects of ethyl esters are compared with the naturally occurring EPA and DHA triacylglycerols present in fish or fish oils which are of interest in primary prevention of cardiovascular disorders.

Risk stratification by the "EPA+DHA level" and the "EPA/AA ratio" focus on anti-inflammatory and antiarrhythmogenic effects of long-chain omega-3 fatty acids.

The identification of risks associated with sudden cardiac death requires further investigations. The question was addressed whether parameters can be established which not only describe an increased risk for an enhanced electrical instability of the heart but also of inflammatory events underlying plaque rupture. Emphasis is placed on dose-dependent effects of the long-chain omega-(omega-)3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Since free acids of EPA and DHA are required for most of their biological effects, it appears essential not only to build up stores in the body for release of these fatty acids, but also to provide a sustained uptake of EPA and DHA in the form of ethyl esters. In contrast to rapidly absorbed triacylglycerols from fish, ethyl esters are taken up more slowly within 24 h. For the administration of 1 g/day highly purified EPA+DHA ethyl esters (Omacor) to healthy volunteers, it is shown that EPA is increased from 0.6% to 1.4% within 10 days, while DHA is increased from 2.9% to 4.3%. After withdrawal, EPA and DHA approach baseline values within 10 days. A gas chromatographic procedure was established which requires only 10 microl of whole blood for the identification of more than 35 fatty acids. Evidence is summarized strengthening the concept that a low "EPA+DHA level" presents a risk for sudden cardiac death and that the administration of 840 mg/day of EPA+DHA ethyl esters raises the "EPA+DHA level" to approximately 6% that is associated with a marked protection from sudden cardiac death. For reducing pro-inflammatory eicosanoids and cytokines, a higher "EPA+DHA level" is required which can be achieved with an intake of 2-4 g/day of 84% EPA+DHA ethyl esters. For assessing influences from pro-inflammatory eicosanoids and cytokines, the EPA/arachidonic acid ratio ("EPA/AA ratio") was identified as diagnostic parameter. To assess the dietary EPA+DHA intake, fatty acids were determined in fish dishes of the cafeteria of the Philipps University Hospital Marburg, Germany. The EPA+DHA content of the popular Alaska Pollock was 125 +/- 70 mg/100 g. A once daily fish dish can thus not provide the 840 mg/day EPA+DHA administered in the GISSI Prevention Study in the form of ethyl ester which markedly reduced the risk of sudden cardiac death in postmyocardial infarction patients. Nonetheless, at least two preferably oily fish meals per week should be consumed as preventive measure by persons without coronary artery disease. With documented coronary heart disease, it was advised to consume approximately 1 g/day of EPA+DHA.