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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

Ferrokinetic studies with stable isotopes as tracers.

A methodology for ferrokinetic studies based on the administration of iron stable isotopes was developed. Fractional plasma clearance and intestinal iron absorption in rabbits were determined using the double tracer technique. Three rabbits were given 58Fe solution intravenously and about 40 min later 57Fe solution orally. Blood samples were drawn at different times following administration. The analysis of the single iron isotopes content in plasma samples was made by proton nuclear activation. The results were compared with those obtained from the administration, to the same rabbits, of the radioactive isotopes 55Fe and 59Fe. The agreement was found to be satisfactory.

An iron metabolism study in humans by means of stable tracers.

An investigation of iron metabolism in a female patient volunteer by administration of stable iron isotopes as tracers was performed. The applied methodology had already been tested in rabbits in comparison with radioactive tracer technique. The subject under study was given 58Fe solution intravenously and about 45 min later 57Fe solution orally. Ten blood samples were drawn at different times within 522 min from injection. Single iron isotopes content in plasma samples was determined by proton nuclear activation. A Compton suppressor system was utilized to improve the detector limits. The characteristic parameters of iron plasma clearance and of iron intestinal absorption were determined.

Molybdenum metabolism studied by means of stable tracers.

An investigation on molybdenum metabolism by administration of molybdenum stable isotopes was performed. Fractional intestinal absorption was determined in animals by the double tracer technique. The investigated subjects were given an enriched solution of Mo-96 orally and, a few minutes later, an enriched solution of Mo-95 intravenously. Blood samples were drawn at different times following the tracer administration. The Mo-95 and Mo-96 contents in plasma samples were determined by proton nuclear activation. The described methodology offers a means for the study of molybdenum metabolism in humans without radiation risk.

Proton activation analysis of stable isotopes for a molybdenum biokinetics study in humans.

Molybdenum is a trace element essential to life. Nevertheless, little information is available on its metabolism in humans. A methodology based on stable isotope administration that combines compartmental analysis, simultaneous use of two tracers, and proton nuclear activation (PNA) is presented. A four-compartment metabolic model was adopted. The compartments are stomach, small intestine, transfer compartment, and unquantified tissue pool. The employment of two different stable isotopes of the element under investigation as tracers was made possible by PNA. Optimization of the technique for molybdenum determination in plasma led to the choice of 95Mo and 96Mo as tracers. Their concentrations in plasma can be determined measuring the disintegration gamma lines of the corresponding technetium radioisotopes produced via (p,n) reaction. In the adopted experimental conditions, a minimum detectable concentration of 2 ng isotope/ml plasma was attained. A kinetics study was performed on two healthy volunteers. To both subjects one tracer was orally administered, and the other intravenously injected. Venous blood samples were withdrawn at different postinjection times and the concentrations for both isotopes determined. The model parameters describing molybdenum kinetics were obtained for the two individuals. Total absorbed fraction was found to be 0.84 +/- 0.03 and 0.86 +/- 0.07, respectively.

Dose-response curve slope improvement and result reproducibility of ferrous-sulphate-doped gels analysed by NMR imaging.

Ferrous sulphate gel analysed by relaxation time measurements with NMR imaging is considered a useful dosimeter for 3D determinations of absorbed dose. A protocol for the gel preparation with agarose SeaPlaque that leads to a dosimeter with very high dose sensitivity is described. The dose-response curve slope is about 0.2 s(-1) Gy(-1) and the G factor turns out to be approximately 185 ions per 100 eV of absorbed energy. A method for making the measurements and analysing the results that brings about good result reproducibility is suggested. A thorough experimental study of the dependence of the dosimeter response on the elapsed time from preparation to irradiation and from irradiation to NMR measurement has revealed good reproducibility. The above characteristic of the gel system is very interesting, because it shows the possibility of utilizing the dosimeter for absolute dose determinations with satisfactory reliability.

Response to a single oral test of molybdenum stable isotopes for absorption studies in humans.

Two volunteer subjects were given orally enriched solutions of Mo-95 and Mo-96 respectively. Blood samples were drawn at various times following the tracer administration. The Mo-95 and Mo-96 content in plasma samples was determined by proton nuclear activation and the response to the single oral test of enriched stable molybdenum isotopes was determined. Assuming a simple two-open-compartment model where the first compartment is the gastrointestinal tract and the other is the plasma, an indicative value of the fractional intestinal absorption for the two subjects is given. The feasibility of direct quantitative measurements of Mo intestinal absorption by the double-tracer technique, using stable tracers, is evidenced.