Long-term effects of somatostatin analogues in rat GH-secreting pituitary tumor cell lines.

PURPOSE: First-generation somatostatin analogs, octreotide (OCT) and lanreotide, are the cornerstone for the medical treatment of growth hormone (GH)-secreting pituitary tumors. A new multireceptor analog, such as pasireotide (PAS), showed better activity than OCT in long-term treatment of patients with acromegaly, but modulation of intracellular key processes is still unclear in vitro. In this study, we evaluated the antitumor activity of OCT and PAS in two GH-secreting pituitary tumor cell lines, GH3 and GH4C1, after a long-term incubation. METHODS: The effects of PAS and OCT on the cell viability, cell cycle, apoptosis, GH secretion, and tumor-induced angiogenesis have been evaluated through a colorimetric method (MTS Assay), DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, ELISA assay and zebrafish platform, respectively. RESULTS: PAS showed a more potent antitumor activity compared to OCT in GH3 cell line exerted through inhibition of cell viability, perturbation of cell cycle progression, and induction of apoptosis after 6 days of incubation. A concomitant decrease in GH secretion has been observed after 2 days of incubation only with PAS. No effect on tumor-induced angiogenesis has been reported after treatment with OCT or PAS in zebrafish/tumor xenograft model. CONCLUSION: Long-term incubation with PAS showed a more potent antitumor activity than that reported after OCT in GH3 cells, mainly modulated by a cell cycle perturbation and a relevant induction in apoptosis.

Ethical aspects in the use of radiation in medicine: update from ICRP Task Group 109.

Whereas scientific evidence is the basis for recommendations and guidance on radiological protection, professional ethics is critically important and should always guide professional behaviour. The International Commission on Radiological Protection (ICRP) established Task Group 109 to advise medical professionals, patients, families, carers, the public, and authorities about the ethical aspects of radiological protection of patients in the diagnostic and therapeutic use of radiation in medicine. Occupational exposures and research-related exposures are not within the scope of this task group. Task Group 109 will produce a report that will be available to the different interested parties for consultation before publication. Presently, the report is at the stage of a working document that has benefitted from an international workshop organised on the topic by the World Health Organization. It presents the history of ethics in medicine in ICRP, and explains why this subject is important, and the benefits it can bring to the standard biomedical ethics. As risk is an essential part in decision-making and communication, a summary is included on what is known about the dose-effect relationship, with emphasis on the associated uncertainties. Once this theoretical framework has been presented, the report becomes resolutely more practical. First, it proposes an evaluation method to analyse specific situations from an ethical point of view. This method allows stakeholders to review a set of six ethical values and provides hints on how they could be balanced. Next, various situations (e.g. pregnancy, elderly, paediatric, end of life) are considered in two steps: first within a realistic, ethically challenging scenario on which the evaluation method is applied; and second within a more general context. Scenarios are presented and discussed with attention to specific patient circumstances, and on how and which reflections on ethical values can be of help in the decision-making process. Finally, two important related aspects are considered: how should we communicate with patients, family, and other stakeholders; and how should we incorporate ethics into the education and training of medical professionals?

ICRP Publication 138: Ethical Foundations of the System of Radiological Protection.

Abstract ­: Despite a longstanding recognition that radiological protection is not only a matter of science, but also ethics, ICRP publications have rarely addressed the ethical foundations of the system of radiological protection explicitly. The purpose of this publication is to describe how the Commission has relied on ethical values, either intentionally or indirectly, in developing the system of radiological protection with the objective of presenting a coherent view of how ethics is part of this system. In so doing, it helps to clarify the inherent value judgements made in achieving the aim of the radiological protection system as underlined by the Commission in Publication 103. Although primarily addressed to the radiological protection community, this publication is also intended to address authorities, operators, workers, medical professionals, patients, the public, and its representatives (e.g. NGOs) acting in the interest of the protection of people and the environment. This publication provides the key steps concerning the scientific, ethical, and practical evolutions of the system of radiological protection since the first ICRP publication in 1928. It then describes the four core ethical values underpinning the present system: beneficence/ non-maleficence, prudence, justice, and dignity. It also discusses how these core ethical values relate to the principles of radiological protection, namely justification, optimisation, and limitation. The publication finally addresses key procedural values that are required for the practical implementation of the system, focusing on accountability, transparency, and inclusiveness. The Commission sees this publication as a founding document to be elaborated further in different situations and circumstances.

Antitumor activity of interferon-ß1a in hormone refractory prostate cancer with neuroendocrine differentiation.

PURPOSE: Type I interferons (IFN-α and IFN-ß) are a class of cytokines that exert several biological activities, such as modulation of cell proliferation and differentiation and of the immune system. Although these cytokines interact with a common receptor complex, IFN-ß showed a more potent antitumor activity than IFN-α in several tumor models. New recombinant human IFN-ß products, such as IFN-ß1a and IFN-ß1b, have been produced in order to improve the stability and bioavailability of natural IFN-ß. In this report, we analyzed the effects of recombinant IFN-ß1a on the cell proliferation of two human androgen-resistant prostate cancer cell lines with neuroendocrine differentiation (DU-145, PC-3) and related mechanisms of action. METHODS: The effects of IFN-ß1a on the cell growth proliferation, cell cycle, and apoptosis have been evaluated in DU-145 and PC-3 cells through MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, respectively. Moreover, the expression of neuron-specific enolase (NSE), cleaved caspase-3, caspase-8, and PARP was evaluated through Western blotting. RESULTS: IFN-ß1a showed a significant anti-proliferative activity in both androgen-resistant cell lines. This effect was related to cell cycle perturbation and induction in apoptosis, as shown by flow cytometric analysis, the activation of caspase-3 and caspase-8 and PARP cleavage during incubation with IFN-ß1a. Moreover, this cytokine reduced the expression of NSE in both cell lines. CONCLUSIONS: Recombinant IFN-ß1a (Rebif) showed a potent in vitro anti-proliferative activity in androgen-resistant prostate cancer cells, and it could represent a promising tool for the treatment of this tumor.

A Review of Healthcare Failure Mode and Effects Analysis (HFMEA) in Radiotherapy.

This paper presents a review of risk analyses in radiotherapy (RT) processes carried out by using Healthcare Failure Mode Effect Analysis (HFMEA) methodology, a qualitative method that proactively identifies risks to patients and corrects medical errors before they occur. This literature review was performed to provide an overview of how to approach the development of HFMEA applications in modern RT procedures, comparing recently published research conducted to support proactive programs to identify risks. On the basis of the reviewed literature, the paper suggests HFMEA shortcomings that need to be addressed.

Implications of the implementation of the revised dose limit to the lens of the eye: the view of IRPA professionals.

In April 2011, the International Commission on Radiological Protection issued a statement on reduction of the equivalent dose limits for the lens of the eye, and strongly recommended its consideration in the revision of the International Atomic Energy Agency's International Basic Safety Standards on Radiation Protection. The reduced dose limit was incorporated in the final version of the Basic Safety Standards. As significant concern was expressed by radiation protection professionals worldwide, the International Radiation Protection Association (IRPA) established a task group to assess the impact of implementation of the revised dose limit for the lens of the eye for occupational exposure. IRPA Associate Societies (ASs) were asked for their views using a questionnaire addressing three topics: implications for dosimetry, implications for methods of protection, and wider implications. The responses received indicate various methods of approach and express different points of view, reflecting nuances of particular ASs or specific professional groups. Topic experts nominated by ASs were selected to assist with collation of responses, and a report was produced by the task group. Conclusions were drawn on the three issues, including potential cost implications. A number of recommendations were drawn from the responses received including: the request for more understanding about the relationship between exposure of the lens of the eye and cataract formation, and further guidance to assist implementation; the importance of economic and social considerations when introducing the limits into national regulations; the need to propose or define procedures related to employment of people with existing or pre-cataract conditions; and the practical aspects relating to dosimetry and protective equipment.

Implications in dosimetry of the implementation of the revised dose limit to the lens of the eye.

In 2012, International Radiation Protection Association (IRPA) established a Task Group to provide an assessment of the impact of the implementation of the ICRP-revised dose limit for the lens of the eye for occupational exposure. Associated Societies (ASs) of IRPA were asked to provide views and comments on the basis of a questionnaire addressing three principal topics: (i) implications for dosimetry, (ii) implications for methods of protection and (iii) wider implications of implementing the revised limits. A summary of the collated responses regarding dosimetry is presented and discussed. There is large agreement on the most critical aspects and difficulties in setting up an appropriate monitoring programme for the lens of the eyes. The recent international standards and technical documents provide guidance for some of the concerns but other challenges remain in terms of awareness, acceptance and practicalities.

Units related to radiation exposure and radioactivity in mass media: the Fukushima case study in Europe and Russia.

Using an analysis of the way European newspapers covered the Fukushima nuclear accident, this article explores how the mass media transmit information about radiation risks from experts to the general public. The study applied a media content analysis method on a total of 1340 articles from 12 leading newspapers in 6 countries: Belgium (N = 260), Italy (N = 270), Norway (N = 133), Russia (N = 172), Slovenia (N = 190) and Spain (N = 315). All articles analysed were selected as being directly or indirectly related to the Fukushima accident by containing the word 'nuclear' and/or 'Fukushima' and were published between the 11th March and the 11th May 2011. The data presented here focus specifically on a cross-cultural comparison of the way the media use quantitative units. Results suggest that although experts are accustomed to communicating about radiological risks in technical language, often using quantitative units to describe the risks, mass media do not tend to use these units in their reporting. Although the study found a large variation in the measurement units used in different countries, it appeared that journalists in all the analysed countries preferred to describe radioactivity by comparing different radiation exposures, rather than reporting the actual measured units. The paper concludes with some practical guidelines for sound public communication about radiation risks.

Report of Task Group on the implications of the implementation of the ICRP recommendations for a revised dose limit to the lens of the eye.

This report was commissioned by the IRPA President to provide an assessment of the impact on members of IRPA Associate Societies of the introduction of ICRP recommendations for a reduced dose limit for the lens of the eye. The report summarises current practice and considers possible changes that may be required. Recommendations for further collaboration, clarification and changes to working practices are suggested.

Minimising activity and dose with enhanced image quality by radiopharmaceutical administrations.

Owing to the introduction of new diagnostic procedures, such as computed tomography (CT), positron emission tomography (PET) and single photon emission computed tomography (SPECT), the individual dose caused by medical exposures has grown rapidly in the last years. This is especially a subject to radiation protection for nuclear medical diagnosis, since in this case radiopharmaceuticals are administered to the patient, meaning not only a radiation exposure to the diseased tissue but also to the healthy tissues of large parts of the body. 'Minimizing Activity and Dose with Enhanced Image quality by Radiopharmaceutical Administrations' (MADEIRA) is a project cofunded by the European Commission within the Seventh Euratom Framework Programme that aims to improve three-dimensional (3D) nuclear medical imaging technologies significantly. MADEIRA is aiming to improve the efficacy and safety of 3D PET and SPECT functional imaging by optimising the spatial resolution and the signal-to-noise ratio, improving the knowledge of the temporal variation of the radiopharmaceuticals' uptake in and clearance from tumourous and healthy tissues, and evaluation of the corresponding patient dose. Using an optimised imaging procedure that improves the information gained per unit administered dose, MADEIRA aims especially to reduce the dose to healthy tissues of the patient. In this paper, an overall summary of the current achievements will be presented.

Neutron- and photon-activation detection limits in breast milk analysis for prospective dose evaluation of the suckling infant.

Complex situations related to the environment, as in the regions affected by the Chernobyl accident and regions in which nuclear weapons testing were undertaken, as in Semipalatinsk, could be reflected in the trace element content in mothers' milk. The evaluation of fractional transfer to milk of ingested or inhaled activity and of the corresponding dose coefficients for the infant, following a mothers' radioactive intake, can take advantage from wide-ranging studies of elemental and radionuclide contents in mothers' milk. In this work the possibility to determine elements, such as Ru, Zr, Nb, Te, Ce, Th, U, in milk powder has been investigated. Although results from elemental analyses of breast milk are to be found in the literature, the determination of the identified elements has attracted poor attention since they are not considered essential elements from a biological point of view. Nevertheless, in the case of radioactive releases to the environment, such data could be of interest in evaluation of dose to the breast-fed infant.

Measurement techniques for tracer kinetic studies with stable isotopes of zirconium.

Biokinetic models are used in radiation protection to assess internal radiation doses. Experiments with stable isotopes as tracers can be performed to obtain characteristic parameters of these models. Two methods for the measurement of zirconium isotopes in human biological samples are presented--thermal ionisation mass spectrometry (TIMS) and proton nuclear activation analysis (PNA). Descriptions include sample preparation, operating conditions, relative uncertainties and method detection limits as well as important properties of both methods.

Coordination of research on internal dosimetry in Europe: the CONRAD project.

The EUropean RAdiation DOSimetry Group (EURADOS) initiated in 2005 the CONRAD Project, a Coordinated Network for Radiation Dosimetry funded by the European Commission (EC), within the 6th Framework Programme (FP). The main purpose of CONRAD is to generate a European Network in the field of Radiation Dosimetry and to promote both research activities and dissemination of knowledge. The objective of CONRAD Work Package 5 (WP5) is the coordination of research on assessment and evaluation of internal exposures. Nineteen institutes from 14 countries participate in this action. Some of the activities to be developed are continuations of former European projects supported by the EC in the 5th FP (OMINEX and IDEAS). Other tasks are linked with ICRP activities, and there are new actions never considered before. A collaboration is established with CONRAD Work Package 4, dealing with Computational Dosimetry, to organise an intercomparison on Monte Carlo modelling for in vivo measurements of (241)Am deposited in a knee phantom. Preliminary results associated with CONRAD WP5 tasks are presented here.

The work of the CONRAD task group 5.2: research studies on biokinetic models.

The objective of this Task Group is the coordination of research studies on biokinetic models and the evaluation of the implications of new biokinetic models on dose assessment and safety standards. For this the new ICRP models, which will be used for a revision of ICRP Publications 30, 54, 68 and 78, are implemented into six different computer codes in five European countries and quality assured by intercomparison procedures. The work has started with the implementation of the new ICRP Alimentary Tract Model. New systemic models and the new NCRP wound model will follow. The work also includes the evaluation of experimental results in terms of formulation by the new model structures and a quality assurance of model formulation.

Determination of dose rates from natural radionuclides in dental materials.

Different types of materials used for dental prosthetics restoration, including feldspathic ceramics, glass ceramics, zirconia-based ceramics, alumina-based ceramics, and resin-based materials, were investigated with regard to content of natural radionuclides by means of thermoluminescence beta dosimetry and gamma spectrometry. The gross beta dose rate from feldspathic and glass ceramics was about ten times higher than the background measurement, whereas resin-based materials generated negligible beta dose rate, similarly to natural tooth samples. The specific activity of uranium and thorium was significantly below the levels found in the period when addition of uranium to dental porcelain materials was still permitted. The high-beta dose levels observed in feldspathic porcelains and glass ceramics are thus mainly ascribable to (40)K, naturally present in these specimens. Although the measured values are below the recommended limits, results indicate that patients with prostheses are subject to higher dose levels than other members of the population. Alumina- and zirconia-based ceramics might be a promising alternative, as they have generally lower beta dose rates than the conventional porcelain materials. However, the dosimetry results, which imply the presence of inhomogeneously distributed clusters of radionuclides in the sample matrix, and the still unsuitable structural properties call for further optimization of these materials.

The use of alpha-Al2O3:C in Risø OSL single grains attachment system for assessing the spatial dose rate distribution due to incorporation of 90Sr in human teeth.

The possibility of using a single grain OSL attachment system developed by the Risø National Laboratory (Roskilde, Denmark) for assessing the spatial distribution of radionuclides incorporated in human tissues was investigated. Detectors containing arrays of single grains of alpha-Al2O3)C powder (Landauer Inc., USA) were prepared using aluminium discs (diameter 9.7 mm), which can accommodate 100 single grains in 0.3 mm holes positioned in a 10 x 10 grid. The luminescence and dosimetric properties of each grain were investigated by exposing the detectors to uniform photon radiation fields. After the characterisation of the detectors, the systems were tested to assess the spatial dose rate distribution because of 90Sr incorporated in a tooth sample extracted from an inhabitant of the Techa River region.

Influence of the chemical form on the plasma clearance of ruthenium in humans.

The radioisotopes of ruthenium (103Ru and 106Ru) are abundant fission products and represent a radiological risk for the population in case of nuclear accidents. Few biokinetic studies have been performed on humans up to now and consequently the current model recommended by ICRP for ruthenium is derived mainly by extrapolation from animal data. The stable isotope 101Ru and proton activation analysis have been used to study the biokinetics of Ru in blood plasma samples taken during 8 studies in three healthy volunteers. The results obtained demonstrated that complexed Ru (in the form of citrate Ru(IV) complexes) is cleared from blood plasma very rapidly (characteristic half time of 17+/-2 min), while inorganic Ru remains longer in the systemic circulation, and is transferred to other organs and/or excreted with a biological half time of 23+/-2h. Good reproducibility of the clearance curves indicated no evidence of inter- or intra-individual variability when the same Ru solution was injected in repeated experiments to different subjects.

Stable tracer investigations in humans for assessing the biokinetics of ruthenium and zirconium radionuclides.

The interest in the biokinetics of ruthenium and zirconium in humans is justified by the potential radiological risk represented by their radionuclides. Only a few data related to the biokinetics of ruthenium and zirconium in humans are available and, accordingly, the biokinetic models currently recommended by the ICRP for these elements are mainly based on data from animal experiments. The use of stable isotopes as tracers, coupled with a proper analytical technique (nuclear activation analysis with protons) for their determination in biological samples, represents an ethically acceptable methodology for biokinetic investigations, being free from any radiation risk for the volunteer subjects. In this work, the results obtained in eight biokinetic investigations for ruthenium, conducted on a total of three healthy volunteers, and six for zirconium, performed on a total of three subjects, are presented and compared to the predictions of the ICRP models.

Sensitivity analysis techniques applied to a revised model of molybdenum biokinetics.

A revised model of molybdenum biokinetics in humans was recently developed on the basis of experimental data gathered in specific investigations conducted with stable tracers. The model can be used for radiation protection purposes, and it is also a suitable working tool for designing new investigations aimed at further improvements to the model. For the latter goal, a sensitivity analysis was performed in order to determine the most significant model parameters in relation to output measurements performed in studies of molybdenum metabolism. A typical sensitivity analysis approach was adopted, considering the effects in variation of model parameters on the time courses of model outputs such as urinary excretion and blood clearance. A recent new sensitivity technique was considered too, based on the calculation of the so-called generalised sensitivity functions. This combines the sensitivities of the model output with respect to model parameters (as in the typical sensitivity analysis method), with the sensitivities of parameter estimates with respect to changes in model outputs. The results obtained in this analysis suggests that data collected in the first 7 h are critical for the definition of the process of blood clearance and related parameters, whereas reliable information at later times is required for a proper characterisation of urinary excretion.

A re-evaluation of the biokinetics of zirconium in humans.

There is much interest in understanding the biokinetics of zirconium in humans due to the potential radiological risk represented by the radionuclide 95Zr and by its daughter 95Nb. Despite the significance of zirconium, few data are available on the actual biokinetics of zirconium in humans. Accordingly the biokinetic model currently recommended by ICRP for this element is based mainly on data from animal experiments. In this study, the use of the stable isotopes 90Zr and 96Zr as tracers has enabled the conduct of 6 biokinetic investigations in 3 healthy volunteers. These studies have provided new valuable information about intestinal absorption and kinetics in blood plasma of zirconium and have been used for the set-up of a more realistic compartmental model with possible applications for dosimetric purposes.