Targeting immune response with therapeutic vaccines in premalignant lesions and cervical cancer: hope or reality from clinical studies.

Human papillomavirus (HPV) is widely known as a cause of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN). HPVs related to cancer express two main oncogenes, i.e. E6 and E7, considered as tumorigenic genes; their integration into the host genome results in the abnormal regulation of cell cycle control. Due to their peculiarities, these oncogenes represent an excellent target for cancer immunotherapy. In this work the authors highlight the potential use of therapeutic vaccines as safe and effective pharmacological tools in cervical disease, focusing on vaccines that have reached the clinical trial phase. Many therapeutic HPV vaccines have been tested in clinical trials with promising results. Adoptive T-cell therapy showed clinical activity in a phase II trial involving advanced CC patients. A phase II randomized trial showed clinical activity of a nucleic acid-based vaccine in HPV16 or HPV18 positive CIN. Several trials involving peptide-protein-based vaccines and live-vector based vaccines demonstrated that these approaches are effective in CIN as well as in advanced CC patients. HPV therapeutic vaccines must be regarded as a therapeutic option in cervical disease. The synergic combination of HPV therapeutic vaccines with radiotherapy, chemotherapy, immunomodulators or immune checkpoint inhibitors opens a new and interesting scenario in this disease.

Achievements in workplace neutron dosimetry in the last decade: lessons learned from the EVIDOS project.

The availability of active neutron personal dosemeters has made real time monitoring of neutron doses possible. This has obvious benefits, but is only of any real assistance if the dose assessments made are of sufficient accuracy and reliability. Preliminary assessments of the performance of active neutron dosemeters can be made in calibration facilities, but these can never replicate the conditions under which the dosemeter is used in the workplace. Consequently, it is necessary to assess their performance in the workplace, which requires the field in the workplace to be fully characterised in terms of the energy and direction dependence of the fluence. This paper presents an overview of developments in workplace neutron dosimetry but concentrates on the outcomes of the EVIDOS project, which has made significant advances in the characterisation of workplace fields and the analysis of dosemeter responses in those fields.

Neutron area survey instrument measurements in the EVIDOS project.

Neutron survey instruments have been exposed at all the measurement locations used in the EVIDOS project. These results have an important impact in the interpretation of the results from the project, since operationally the survey instrument will be used for an initial assessment of and routine monitoring of the ambient dose equivalent dose rate. Additionally, since the response of these instruments is in some cases very well characterised, their systematic deviations from the reference quantities provide an important verification of the determination of those quantities.

Characterisation of mixed neutron photon workplace fields at nuclear facilities by spectrometry (energy and direction) within the EVIDOS project.

Within the EC project EVIDOS, 17 different mixed neutron-photon workplace fields at nuclear facilities (boiling water reactor, pressurised water reactor, research reactor, fuel processing, storage of spent fuel) were characterised using conventional Bonner sphere spectrometry and newly developed direction spectrometers. The results of the analysis, using Bayesian parameter estimation methods and different unfolding codes, some of them especially adapted to simultaneously unfold energy and direction distributions of the neutron fluence, showed that neutron spectra differed strongly at the different places, both in energy and direction distribution. The implication of the results for the determination of reference values for radiation protection quantities (ambient dose equivalent, personal dose equivalent and effective dose) and the related uncertainties are discussed.

Application of workplace correction factors to dosemeter results for the assessment of personal doses at nuclear facilities.

Ratios of H(p)(10) and H*(10) were determined with reference instruments in a number of workplace fields within the nuclear industry and used to derive workplace-specific correction factors. When commercial survey meter results together with these factors were applied to the results of the locally used personal dosemeters their results improved and became within 0.7 and 1.7 of the reference values or better depending on the response of the survey meter. A similar result was obtained when a correction was determined with a prototype reference instrument for H(p)(10) after adjustment of its response. Commercially available survey instruments both for photon and neutron H*(10) measurements agreed with the reference instruments in most cases to within 0.5-1.5. Those conclusions are derived from results reported within the EC supported EVIDOS contract.

Evaluation of individual dosimetry in mixed neutron and photon radiation fields (EVIDOS). Part I: Scope and methods of the project.

Supported by the European Commission, the EVIDOS project started in November 2001 with the broad goal of evaluating state of the art dosimetry techniques in representative workplaces of the nuclear industry. Seven European institutes joined efforts with end users at nuclear power plants, at fuel processing and reprocessing plants, and at transport and storage facilities. A comprehensive programme was devised to evaluate capabilities and limitations of standard and innovative personal dosemeters in relation to the mixed neutron-photon fields of concern to the nuclear industry. This paper describes the criteria behind the selection of dosimetry techniques and workplaces that were analysed, as well as the organisation of the measurement campaigns. Particular emphasis was placed on the evaluation of a variety of electronic personal dosemeters, either commercially available or previously developed by the partners. The estimates provided by these personal dosemeters were compared to reference values of dose equivalent quantities derived from spectrometry and fluence-to-dose equivalent conversion coefficients. Spectrometry was performed both with conventional multisphere and with some original instrumentation providing energy and direction resolution, based on silicon detectors and superheated drop detectors mounted on or in spherical moderators. The results were collected in a large, searchable database and are intended to be used in the harmonisation of dosimetric procedures for mixed radiation fields and for the approval of dosimetry services in Europe.

Summary of personal neutron dosemeter results obtained within the EVIDOS project.

Within the EC project EVIDOS ('Evaluation of Individual Dosimetry in Mixed Neutron and Photon Radiation Fields'), different types of active neutron personal dosemeters (and some passive ones) were tested in workplace fields at nuclear installations in Europe. The results of the measurements which have been performed up to now are summarised and compared to our currently best estimates of the personal dose equivalent Hp(10). Under- and over-readings by more than a factor of two for the same dosemeter in different workplace fields indicate that in most cases the use of field-specific correction factors is required.

Direction distributions of neutrons and reference values of the personal dose equivalent in workplace fields.

Within the EC project EVIDOS, double-differential (energy and direction) fluence spectra were determined by means of novel direction spectrometers. By folding the spectra with fluence-to-dose equivalent conversion coefficients, contributions to H*(10) for 14 directions, and values of the personal dose equivalent Hp(10) and the effective dose E for 6 directions of a person's orientation in the field were determined. The results of the measurements and calculations obtained within the EVIDOS project in workplace fields in nuclear installations in Europe, i.e., at Krümmel (boiling water reactor and transport cask), at Mol (Venus research reactor and fuel facility Belgonucléaire) and at Ringhals (pressurised reactor and transport cask) are presented.

Evaluation of individual dosimetry in mixed neutron and photon radiation fields (EVIDOS). Part II: Conclusions and recommendations.

The paper presents the main conclusions and recommendations derived from the EVIDOS project, which is supported by the European Commission within the 5th Framework Programme. EVIDOS aims at evaluating state of the art neutron dosimetry techniques in representative workplaces of the nuclear industry with complex mixed neutron-photon radiation fields. This analysis complements a series of individual papers which present detailed results and it summarises the main findings from a practical point of view. Conclusions and recommendations are given concerning characterisation of radiation fields, methods to derive radiation protection quantities and dosemeter results.

Evaluation of individual monitoring in mixed neutron/photon fields: mid-term results from the EVIDOS project.

EVIDOS is an EC sponsored project that aims at an evaluation and improvement of radiation protection dosimetry in mixed neutron/photon fields. This is performed through spectrometric and dosimetric investigations during different measurement campaigns in representative workplaces of the nuclear industry. The performance of routine and, in particular, novel personal dosemeters and survey instruments is tested in selected workplace fields. Reference values for the dose equivalent quantities, H(*)(10) and H(p)(10) and the effective dose E, are determined using different spectrometers that provide the energy distribution of the neutron fluence and using newly developed devices that determine the energy and directional distribution of the neutron fluence. The EVIDOS project has passed the mid-term, and three measurement campaigns have been performed. This paper will give an overview and some new results from the third campaign that was held in Mol (Belgium), around the research reactor VENUS and in the MOX producing plant of Belgonucléaire.

Electronic neutron personal dosemeters: their performance in mixed radiation fields in nuclear power plants.

This work describes spectral distributions of neutrons obtained as function of energy and direction at four workplace fields at the Krümmel reactor in Germany. Values of personal dose equivalent H(p)(10) and effective dose E are determined for different directions of a person's orientation in these fields and readings of personal neutron dosemeters--especially electronic dosemeters--are discussed with respect to H(p)(10) and E.

A neutron dosemeter for nuclear criticality accidents.

A neutron dosemeter which offers instant read-out has been developed for nuclear criticality accidents. The system is based on gels containing emulsions of superheated dichlorodifluoromethane droplets, which vaporise into bubbles upon neutron irradiation. The expansion of these bubbles displaces an equivalent volume of gel into a graduated pipette, providing an immediate measure of the dose. Instant read-out is achieved using an array of transmissive optical sensors which consist of coupled LED emitters and phototransistor receivers. When the gel displaced in the pipette crosses the sensing region of the photomicrosensors, it generates a signal collected on a computer through a dedicated acquisition board. The performance of the device was tested during the 2002 International Accident Dosimetry Intercomparison in Valduc, France. The dosemeter was able to follow the initial dose gradient of a simulated accident, providing accurate values of neutron kerma; however, the emulsion was rapidly depleted of all its drops. A model of the depletion effects was developed and it indicates that an adequate dynamic range of the dose response can be achieved by using emulsions of smaller droplets.

Characterisation of the TAPIRO BNCT epithermal facility.

A collimated epithermal beam for boron neutron capture therapy (BNCT) research has been designed and built at the TAPIRO fast research reactor. A complete experimental characterisation of the radiation field in the irradiation chamber has been performed, to verify agreement with IAEA requirements. Slow neutron fluxes have been measured by means of an activation technique and with thermoluminescent detectors (TLDs). The fast neutron dose has been determined with gel dosemeters, while the fast neutron spectrum has been acquired by means of a neutron spectrometer based on superheated drop detectors. The gamma-dose has been measured with gel dosemeters and TLDs. For an independent verification of the experimental results, fluxes, doses and neutron spectra have been calculated with Monte Carlo simulations using the codes MCNP4B and MCNPX_2.1.5 with the direct statistical approach (DSA). The results obtained confirm that the epithermal beams achievable at TAPIRO are of suitable quality for BNCT purposes.

Individual neutron monitoring in workplaces with mixed neutron/photon radiation.

EVIDOS ('evaluation of individual dosimetry in mixed neutron and photon radiation fields') is an European Commission (EC)-sponsored project that aims at a significant improvement of radiation protection dosimetry in mixed neutron/photon fields via spectrometric and dosimetric investigations in representative workplaces of the nuclear industry. In particular, new spectrometry methods are developed that provide the energy and direction distribution of the neutron fluence from which the reference dosimetric quantities are derived and compared to the readings of dosemeters. The final results of the project will be a comprehensive set of spectrometric and dosimetric data for the workplaces and an analysis of the performance of dosemeters, including novel electronic dosemeters. This paper gives an overview of the project and focuses on the results from measurements performed in calibration fields with broad energy distributions (simulated workplace fields) and on the first results from workplaces in the nuclear industry, inside a boiling water reactor and around a spent fuel transport cask.

Electronic neutron personal dosimetry with superheated drop detectors.

The prototype of an electronic personal neutron dosemeter based on superheated drop detectors is presented. This battery operated device comprises a neutron sensor, bubble-counting electronics and a temperature controller ensuring an optimal dose equivalent response. The neutron sensor is a 12 ml detector vial containing an emulsion of about 50,000 halocarbon-12 droplets of 100 microns diameter. The temperature controller is a low-power, solid-state device stabilising the emulsion at 31.5 degrees C by means of an etched foil heater. The microprocessor controlled counting electronics relies on a double piezo-electric transducer configuration to record bubble formation acoustically via a comparative pulse-shape analysis of ambient noise and detector signals. The performance of the dosemeter was analysed in terms of the requirements presently developed for neutron personal dosemeters. The detection threshold is about 1 microSv, while the personal dose equivalent response to neutrons in the thermal to 62 MeV range falls within a factor 1.6 of 13 bubbles per microSv.

The Italian national survey of aircrew exposure: I. Characterisation of advanced instrumentation.

The survey of aircrew exposure required the characterisation and/or the development of a diverse array of both passive and active instruments, which were not available at any one laboratory. To ensure the availability of the most advanced dosimetric systems and the relevant calibration facilities needed for the survey, an international collaboration was formed, which was facilitated by multinational research contracts promoted by the Commission of the European Communities. Close cooperation among scientists with long-term experience in different disciplines, such as cosmic ray measurement in space and radiation protection dosimetry, made it possible to exploit successfully damage track detectors for the accurate evaluation of very low fluences of particles with high energy and high charges. For a long time, the major concern for the assessment of aircrew exposure has been the accurate evaluation of the cosmic ray neutron dose. In this paper, four different dosimetric systems are considered, the response of which is sensitive to both low and high energy neutrons. All these dosimetric systems have provided consistent results when exposed together to the high energy beam facility at CERN, which is considered to approximate the cosmic ray field.

The Italian national survey of aircrew exposure: II. On-board measurements and results.

The Italian survey of aircrew exposure has been carried out with different advanced dosimetric systems, as described in part I of this paper. The key strategy of the survey was to obtain on-board comparison of measurements for both passive and real-time detectors flown together with passengers. The survey has been carried out in the period of solar minimum (1995-1997), in which the exposure to galactic cosmic rays reaches its maximum value. Even though carrying out the survey in the period of solar minimum was entirely coincidental, this circumstance has been used to good advantage to obtain a comprehensive set of data of the galactic cosmic radiation with little or no disturbance by the solar activity modulation. This comprehensive set of data covers flight routes between -20 degrees and 75 degrees geographic latitude at different civil aviation altitudes. The survey obtained with different advanced dosimetric systems has been supplemented by a large variety of data gathered with passive stacks on different short-range and long-range flights at supersonic and subsonic altitudes. Some of the most important conclusions which can be drawn from the survey are: (i) aircrew of civil aviation receive annual doses within the range of 1 mSv to 6 mSv; (ii) data from different periods of solar minimum agree well, since the discrepancies encountered seem mainly due to the different dosimetric systems used; (iii) repeated measurements on the same route are highly consistent.

A directional dose equivalent monitor for neutrons.

A directional dose equivalent monitor is introduced which consists of a 30 cm diameter spherical phantom hosting a superheated drop detector embedded at a depth of 10 mm. The device relies on the similarity between the fluence response of neutron superheated drop detectors based on halocarbon-12 and the quality-factor-weighted kerma factor. This implies that these detectors can be used for in-phantom dosimetry and provide a direct reading of dose equivalent at depth. The directional dose equivalent monitor was characterised experimentally with fast neutron calibrations and numerically with Monte Carlo simulations. The fluence response was determined at angles of 0, 45, 90, 135 and 180 degrees for thermal to 20 MeV neutrons. The response of the device is closely proportional to the fluence-to-directional dose equivalent conversion coefficient, h'phi (10; alpha, E). Therefore, our monitor is suitable for a direct measurement of neutron directional dose equivalent, H'(10), regardless of angle and energy distribution of the neutron fluence.

In-phantom dosimetry and spectrometry of photoneutrons from an 18 MV linear accelerator.

A combination of three superheated drop detectors with different neutron energy responses was developed to evaluate dose-equivalent and energy distributions of photoneutrons in a phantom irradiated by radiotherapy high-energy x-ray beams. One of the three detectors measures the total neutron dose equivalent and the other two measure the contributions from fast neutrons above 1 and 5.5 MeV, respectively. In order to test the new method, the neutron field produced by the 10 cm X 10 cm x-ray beam of an 18 MV radiotherapy accelerator was studied. Measurements were performed inside a tissue-equivalent liquid phantom, at depths of 1, 5, 10 and 15 cm and at lateral distances of 0, 10, and 20 cm from the central axis. These data were used to calculate the average integral dose to the radiotherapy patient from direct neutrons as well as from neutrons transmitted through the accelerator head. The characteristics of the dosimeters were confirmed by results in excellent agreement with those of prior studies. Track etch detectors were also used and provided an independent verification of the validity of this new technique. Within the primary beam, we measured a neutron entrance dose equivalent of 4.5 mSv per Gy of photons. It was observed that fast neutrons above 1 MeV deliver most of the total neutron dose along the beam axis. Their relative contribution increases with depth, from about 60% at the entrance to over 90% at a depth of 10 cm. Thus, the average energy increases with depth in the phantom as neutron spectra harden.

A multicenter evaluation of a single-pass lead VDD pacing system. The Multicenter Study Group.

Since June 1985 until April 1989, 237 patients (130 males, 107 females, aged 22 to 95 years, mean 71) with symptomatic AV conduction disturbances and competent sinus node, were implanted with a single-pass lead VDD pacing system in 30 centers and followed-up for at least 6 months. The ventricular pacing lead incorporated two atrial ring 3-cm apart electrodes, positioned within the right atrial cavity without contact with the heart wall, in order to detect the atrial activity, which is differentially processed by the pacemaker. At implant, mean atrial electrogram amplitude, derived from a custom pacemaker system analyzer (PSA) with the same input filter of the pacemaker was 1.7 +/- 0.8 mV (n = 93). In all cases, atrial sensitivity at implant was the default value +/- 0.15 mV. The atrial tracking capability of the pacing systems was assessed within the month and every 6 months after implantation by means of clinical evaluation, resting ECG, 24-hour Holter monitoring and the following tests: exercise stress testing, mental stress, isometric exercise, and nifedipine test. These tests evoke an increase of atrial rate in consequence of metabolic needs or as a reflex response. The criterion used to evaluate the correct operation of the system was the percentage of atrial synchronization. This was defined as the ratio between atrial triggered ventricular paced complexes and all ventricular paced complexes. All monitorings showed a ratio higher than or equal to 98% in a percentage of patients not lower than 95%. Mean follow-up was 385 days (range 183-1,370 days).(ABSTRACT TRUNCATED AT 250 WORDS)