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1 In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are 2 responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and 3 Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed 4 to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared to IM alone in 5 CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two 6 patients were randomly assigned to either arm. Treatment ‘successes’ was the primary end-point, 7 defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end-8 points were 24-month treatment ‘successes’, molecular response and progression at 12 and 24 months, 9 comparison of IM levels, and achievement of blood HCQ levels >2000ng/ml. At 12 months, there was no 10 difference in ‘success’ rate (p=0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p=0.21). At 24 11 months, the ‘success’ rate was 20.8% higher with IM/HCQ (p=0.059). No patients progressed. 12 Seventeen adverse events, including four serious adverse reactions, were reported; diarrhoea occurred 13 more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR 14 levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.

Ongoing national programmes and International forums have in recent decades developed and enhanced methods and strategies in how to address the characterisation of potentially suitable sites for radioactive waste repositories. Siting processes, site selection and site investigation programmes have been conducted for near surface and geological repositories and plans for construction are in progress or have already been implemented. Lessons learned from these national and international programmes are available and results are published. In this paper we synthesise the methods and our lessons learned in how to plan, conduct, and achieve site understanding. Effective site understanding should incorporate a multi-disciplinary and integrated view of geosphere and biosphere information for a site, together with the designed parts of a repository or installation that constitute the total system. We argue that this integrated approach, following a staged program of repository development and adopting a graded approach to assessment at each stage, is to be recommended. The recommendation is supported by the results of international cooperation and progress with national programmes (e.g. the Swedish SKB). Further, we argue that this strategy is valid as a foundation for planning and execution of other types of radioactive waste management programmes such as decommissioning, legacy site management and remediation projects.

The management of chronic myeloid leukaemia (CML) has seen considerable change in the last several years. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of CML in adults and children.

Helicobacter spp. are Gram-negative bacteria that cause a spectrum of disease in the gut, biliary tree and liver. Many Helicobacter spp. produce a range of cholesteryl α-glucosides that have the potential to act as pathogen associated molecular patterns. We report a highly stereoselective α-glucosylation of cholesterol using 3,4,6-tri-O-acetyl-2-O-benzyl-d-glucopyranosyl N-phenyl-2,2,2-trifluoroacetimidate, which allowed the synthesis of cholesteryl α-glucoside (αCG) and representative Helicobacter spp. cholesteryl 6-O-acyl-α-glucosides (αCAGs; acyl = C12:0, 14:0, C16:0, C18:0, C18:1). All αCAGs, irrespective of the nature of their acyl chain composition, strongly agonised signalling through the C-type lectin receptor Mincle from human and mouse to similar degrees. By contrast, αCG only weakly signalled through human Mincle, and did not signal through mouse Mincle. These results provide a molecular basis for understanding of the immunobiology of non-pylori Helicobacter infections in humans and other animals.

Radiation doses received by workers during their movement within areas contaminated as a result of events and activities, leading to emergency or existing exposure situations, may provide a substantial contribution to total external exposure during remediation work. This paper describes an approach to minimise worker external exposure in these circumstances, based on graph theory. The paper describes several tasks, including: searching for a route with the lowest dose, searching for an optimal bypass with a given set of control points and searching for the optimal road network coverage. Classical graph theory algorithms have been used (Dijkstra's algorithm, Chinese postman problem and travelling salesman problem). Algorithms for solving the above mentioned problems have been developed and were included in the information-analytical system for radiation safety. This software has been applied for optimisation of protection during remediation work at the Andreeva Bay site of temporary storage for spent fuel and radioactive waste in the Kola Peninsula, both in the context of existing exposure situations and improving the preparedness for emergency exposure situations.

This paper deals with classification of dose distributions of nuclear workers based on antikurtosis (Q) and entropy coefficients (K) and their relationship presented in QK-diagrams. It is shown that determination of the most appropriate distribution to adopt, for a specific data set of a wide range of input data, requires building and analysing QK-diagrams for distributions of logarithms of individual doses. Actual dose distributions for emergency and occupational exposure situations were then considered, as well as doses for one day of work during clean-up and routine activities. It is shown that, in all cases, three types of distributions of logarithms of individual doses were present: normal, Weibull and Chapeau. The location of the representation point of a dose distribution reflects the degree of dose control of the group of workers whose individual doses are collectively displayed in the QK-diagram. The more the representation point of the analysed distribution of the logarithms of the individual dose of a given contingent of workers deviates from the point of the lognormal distribution, the more there was intervention in the process of individual dose accumulation. Thus, QK-diagrams could be used to develop a dose control function. It is shown that the hybrid lognormal distribution, which is widely used in the field of radiation safety, for the purpose of approximation of real dose distributions, is unable to satisfactorily describe many dose distributions arising in aftermath operations and occupational exposure.

Swelled cans of low-acid food were collected from supermarkets over a 17-month period. Microorganisms were recovered from 47% of the 790 containers tested. Calculations suggested that approximately another 47% of the swelled cans were the result of microbial contamination, although no microorganisms were recovered, while 6% were physically induced (nonmicrobiological) swells. Food type appeared to influence the recovery of microorganisms. Types and incidences of organisms recovered were: 91.6% typical leaker spoilage microorganisms, 0.5% thermophiles, and 7.9% pure cultures of sporeforming organisms traditionally associated with under-processing.

Three series of experiments were carried out. Each experiment consisted of six or seven tests where four or five containers were fitted with thermocouples and five were fitted with biological indicator units (BIU). The sterilization value (F0) delivered to cans of peas in brine was calculated from heat penetration data. The heat penetration data were analyzed for test-to-test reproducibility within each experimental series. Sterilization values for all tests were calculated from the BIU test results. The sterilizing values F0 (PHY) determined from physical (PHY) heat penetration data were compared with sterilizing values F0 (BIO) determined using the BIUs, both on the basis of accuracy and variability. The mean F0 (PHY) - F0 (BIO) was + 1.2 min. The mean coefficient of variation of the F0 (PHY) was 0.03 and the F (BIO) was 0.06.

Aims Few reports compare the contribution of the talonavicular articulation to overall range of movement in the sagittal plane after total ankle arthroplasty (TAA) and tibiotalar arthrodesis. The purpose of this study was to assess changes in ROM and functional outcomes following tibiotalar arthrodesis and TAA. Patients and Methods Patients who underwent isolated tibiotalar arthrodesis or TAA with greater than two-year follow-up were enrolled in the study. Overall arc of movement and talonavicular movement in the sagittal plane were assessed with weight-bearing lateral maximum dorsiflexion and plantarflexion radiographs. All patients completed Short Form-12 version 2.0 questionnaires, visual analogue scale for pain (VAS) scores, and the Foot and Ankle Ability Measure (FAAM). Results In all, 41 patients who underwent TAA and 27 patients who underwent tibiotalar arthrodesis were enrolled in the study. The mean total arc of movement was 34.2° (17.0° to 59.1°) with an average contribution from the talonavicular joint of 10.5° (1.2° to 28.8°) in the TAA cohort. The average total arc of movement was 24.3° (6.9° to 44.3°) with a mean contribution from the talonavicular joint of 22.8° (5.6° to 41.4°) in the arthrodesis cohort. A statistically significant difference was detected for both total sagittal plane movement (p = 0.00025), and for talonavicular motion (p < 0.0001). A statistically significant lower VAS score (p = 0.0096) and higher FAAM (p = 0.01, p = 0.019, respectively) was also detected in the TAA group. Conclusion TAA preserves more anatomical movement, has better pain relief and better patient-perceived post-operative function compared with patients undergoing fusion. The relative increase of talonavicular movement in fusion patients may play a role in the outcomes compared with TAA and may predispose these patients to degenerative changes over time. Take home message: TAA preserves more anatomic sagittal plane motion and provides greater pain relief and better patient-perceived outcomes compared with ankle arthrodesis. Cite this article: Bone Joint J 2016;98-B:634–40.

The Coastal Technical Base (CTB) №569 at Andreeva Bay was established in the early 1960s and intended for the refueling of nuclear submarine reactors and temporary storage of spent nuclear fuel (SNF) and radioactive waste (RW). In 2001, the base was transferred to the Russian Ministry for Atomic Energy and the site remediation began. The paper describes in detail the radiation situation change at the technical site in Andreeva Bay from 2002-2016, the period of preparation for the most critical phase of remedial work: removal of spent fuel assemblies. The analysis of aggregated indicators and data mining were used. The article suggests the best number and location of checkpoints needed to ensure sufficient accuracy of the radiation situation description. The fractal properties of the radiation field are studied using the Hurst index. The relationship between checkpoints was assessed using the method of searching for checkpoint communities. The decrease in the integral of the ambient dose equivalent rate (ADER) at the technical site was evaluated by the method of time series decomposition. Three components of time series were identified: trend, seasonal and residual. The trend of the ADER integral over the technical site is a monotonic decreasing function, where the initial and final values differ tenfold. Taking into account that 137Cs dominates the radiation situation on-site, it is clear that the ADER due to the radionuclide decay will have decreased by 1.4 times. It is estimated that only a small proportion of 137Cs has migrated off-site. Therefore, approximately a sevenfold decrease in dose rate is mainly due to remediation activities of personnel. During the year, the seasonal component varies the ADER integral by a factor of two, due to snowfall. The residual component reflects the uncertainty of the ADER integral calculation and phases of active SNF and RW management. The methods developed are used to support the optimization of remediation work as well as regulatory supervision of occupational radiation protection.

In compliance with the fundamentals of the government's policy in the field of nuclear and radiation safety approved by the President of the Russian Federation, Russia has developed a national program for decommissioning of its nuclear legacy. Under this program, the State Atomic Energy Corporation 'Rosatom' is carrying out remediation of a Site for Temporary Storage of spent nuclear fuel (SNF) and radioactive waste (RW) at Andreeva Bay located in Northwest Russia. The short term plan includes implementation of the most critical stage of remediation, which involves the recovery of SNF from what have historically been poorly maintained storage facilities. SNF and RW are stored in non-standard conditions in tanks designed in some cases for other purposes. It is planned to transport recovered SNF to PA 'Mayak' in the southern Urals. This article analyses the current state of the radiation safety supervision of workers and the public in terms of the regulatory preparedness to implement effective supervision of radiation safety during radiation-hazardous operations. It presents the results of long-term radiation monitoring, which serve as informative indicators of the effectiveness of the site remediation and describes the evolving radiation situation. The state of radiation protection and health care service support for emergency preparedness is characterized by the need to further study the issues of the regulator-operator interactions to prevent and mitigate consequences of a radiological accident at the facility. Having in mind the continuing intensification of practical management activities related to SNF and RW in the whole of northwest Russia, it is reasonable to coordinate the activities of the supervision bodies within a strategic master plan. Arrangements for this master plan are discussed, including a proposed programme of actions to enhance the regulatory supervision in order to support accelerated mitigation of threats related to the nuclear legacy in the area.

A thin silicon wafer when illuminated by a Q-switched frequency doubled Nd-YAG laser is used as a very fast ultra-low loss,quasi-optical photo-conductive switch to cavity dump a millimetre-wave open resonator. Initial experiments indicate that itshould be possible to provide short pulses at millimetre-wave frequencies with power gains of several hundred.

Andreeva Bay in northwest Russia hosts one of the former coastal technical bases of the Northern Fleet. Currently, this base is designated as the Andreeva Bay branch of Northwest Center for Radioactive Waste Management (SevRAO) and is a site of temporary storage (STS) for spent nuclear fuel (SNF) and other radiological waste generated during the operation and decommissioning of nuclear submarines and ships. According to an integrated expert evaluation, this site is the most dangerous nuclear facility in northwest Russia. Environmental rehabilitation of the site is currently in progress and is supported by strong international collaboration. This paper describes how the optimization principle (ALARA) has been adopted during the planning of remediation work at the Andreeva Bay STS and how Russian-Norwegian collaboration greatly contributed to ensuring the development and maintenance of a high level safety culture during this process. More specifically, this paper describes how integration of a system, specifically designed for improving the radiological safety of workers during the remediation work at Andreeva Bay, was developed in Russia. It also outlines the 3D radiological simulation and virtual reality based systems developed in Norway that have greatly facilitated effective implementation of the ALARA principle, through supporting radiological characterisation, work planning and optimization, decision making, communication between teams and with the authorities and training of field operators.

Carbon-14 has been identified as one of the more significant radionuclides in solid radioactive wastes in a repository, due to the potential radiological impact arising if 14C were to be released and enter the biosphere. However, the assessment of radiation doses is complicated by the major role of carbon in biological processes, and this has tended to lead to the adoption of a cautious assessment approach.An international comparison of five models used to predict uptake of 14C to agricultural crops has been undertaken, within the BIOPROTA framework. Processes investigated include conversion of 14C-labelled CH4 into CO2 in soils, carbon accumulation in and release from soil carbon pools, gaseous emanation to, and dispersion from, the plant canopy atmosphere and, incorporation into plants by photosynthesis.For a unit rate of entry of 14C to soil, modelled activity concentrations in cereal crops differ by three to five orders of magnitude. This reflects, in part, differing assumptions for mixing and dispersion of air above the soil surface and within the crop canopy layer. For a unit activity concentration of 14C in air, the modelled uptake to cereal crops converges significantly. Following an assumed irrigation of crops with groundwater containing unit activity of 14C, the predicted uptake to crops varied by two to four orders of magnitude, again largely dominated by assumptions regarding the canopy atmosphere. In all cases, there is some convergence in model predictions as field size increases.A continuing programme of field research is being undertaken in parallel with the assessment work.

Consideration of the biosphere is important in the post-closure safety assessment of a geological disposal facility (GDF) as the biosphere acts as the receptor for any contaminants that may be released from the geosphere. Considerable uncertainty exists in the characteristics of the biosphere at times in the far future when any contaminant releases from a GDF would reach the accessible environment. These uncertainties include human behaviour, affecting environmental change as well as exposure modes.A number of critical scientific issues have been identified through the practical application of the International Atomic Energy Agency reference biosphere approach within both site generic and site specific repository assessment projects. These issues are being addressed through an international collaboration programme, BIOPROTA. The purpose of this paper is to describe the BIOPROTA programme, its objectives and typical working method. The approach is illustrated with examples from the recent work programme including model intercomparison studies for the radionuclides 36Cl and 79Se.

New radiocarbon ages for wood samples retrieved from the base of the Acheron rock avalanche near Porters Pass, Canterbury, show a clustering of ages between 1370 and 1101 yr BP. This is significantly dissimilar to the established radiocarbon age of 500±69 yr BP (NZ547), from weathering-rind thickness measurements and from lichen studies. This contradiction impacts on current calibrations of lichenometric and weathering-rind dating methods, which has serious implications for landslide and earthquake dates based on them. A 500–600 yr BP earthquake event along the Porters Pass–Amberley Fault Zone has been dated in an adjacent trench and is consistent with previous dates but does not correspond to the Acheron rock avalanche emplacement as previously proposed. The landslide may have been caused by either a Porters Pass Fault event (1100–800 yr BP) or by the better-constrained Round Top event (1010±50 yr BP) on the Alpine Fault.

The site of temporary storage of spent nuclear fuel and radioactive waste, situated at Andreeva Bay in Northwest Russia, was developed in the 1960s, and it has carried out receipt and storage of fresh and spent nuclear fuel, and solid and liquid radioactive waste generated during the operation of nuclear submarines and nuclear-powered icebreakers. The site is now operated as the western branch of the Federal State Unitary Enterprise, SevRAO. In the course of operation over several decades, the containment barriers in the Spent Nuclear Fuel and Radioactive Waste storage facilities partially lost their containment effectiveness, so workshop facilities and parts of the site became contaminated with radioactive substances. This paper describes work being undertaken to provide an updated regulatory basis for the protection of workers during especially hazardous remediation activities, necessary because of the unusual radiation conditions at the site. It describes the results of recent survey work carried out by the Burnasyan Federal Medical Biophysical Centre, within a programme of regulatory cooperation between the Norwegian Radiation Protection Authority and the Federal Medical-Biological Agency of Russia. The survey work and subsequent analyses have contributed to the development of special regulations setting out radiological protection requirements for operations planned at the site. Within these requirements, and taking account of a variety of other factors, a continuing need arises for the implementation of optimisation of remediation at Andreeva Bay.

Patients with newly diagnosed chronic phase chronic myeloid leukemia were treated with imatinib mesylate (IM) for 6 to 12 months to establish disease control, before reduced intensity stem cell transplantation (RISCT). Escalating doses of donor lymphocyte infusions were given from 6 months after transplantation to eradicate residual disease. A total of 18 patients entered the study and 15 received RISCT (median follow-up, 31 months). RISCT was well tolerated with rapid engraftment, short inpatient stays, and few readmissions. Viral reactivation was common, although extensive graft-versus-host disease occurred infrequently. Donor lymphocyte infusions were given as part of the RISCT protocol in 13 of 15 patients. BCR-ABL transcripts continued to decrease after RISCT, and 8 (53%) patients achieved sustained undetectable levels. All patients are currently off IM. Although IM is now established as first-line therapy for chronic phase chronic myeloid leukemia, this protocol is a safe, well-tolerated, and effective strategy in these patients. This study is registered at http://www.controlled-trials.com as ISRCTN86187144.

In a pilot study of the combination of epirubicin and chlorambucil in the treatment of chronic lymphocytic leukemia (CLL), 10 patients with advanced or progressive disease were treated in four centres. Up to a total of 15 courses in individual patients were given. Toxicity was relatively mild with nausea due to epirubicin being the most commonly reported side-effect. One patient developed a probable septicemia during a period of neutropenia. In another patient who died from probable Pneumocystis carinii pneumonia (PCP) after only one course of therapy, death could not be regarded as necessarily treatment-related. In seven previously untreated patients, one complete response and four partial remissions were seen. All three previously treated patients showed partial remissions.

Reduced intensity conditioning (RIC) for allogeneic stem cell transplantation allows stable donor cell engraftment with the maintenance of a graft versus malignancy effect. Many different regimens exist employing various combinations of chemotherapy, radiotherapy and T-cell depletion. We examined the role of non-T-cell depleted RIC regimens in 56 patients with haematological malignancies. Patients received fludarabine phosphate for 5 days (30 mg/m2 in 35 patients, 25 mg/m2 in 21 patients) and melphalan for 1 day (140 mg/m2 in 36 patients, 100 mg/m2 in 20 patients). Immunosuppression was with CyA alone in 33 patients and CyA/MTX in 23 patients. Twenty-four of the 26 patients with chimerism data showed >95% donor chimerism at 3 months post transplant. aGVHD occurred in 18% of patients receiving CyA/MTX compared to 53% of patients receiving CyA. The 100-day mortality rate was 0.16 (95%CI 0.08–0.28) and 1-year nonrelapse mortality was 0.24 (95%CI 0.13–0.38). Thirty-three patients remained alive and in CR at a median of 19 months post transplant (range 3–38 months). We have shown that patients transplanted with fludarabine phosphate, melphalan 100 mg/m2 and with CyA/MTX as post transplant immunosuppression can achieve good disease control with an acceptable level of toxicity. Further studies are required to confirm these findings.

The 1100-year-old Acheron rock avalanche deposit lies in an active tectonic setting in Canterbury, New Zealand, and has a volume of ten million cubic metres and a runout distance 3.5 km. The deposit comprises intensely fragmented greywacke rock, and the processes of intense rock fragmentation during runout are postulated to have generated an isotropic dispersive stress. Dynamic simulation shows that the runout can be explained as a flow of dry granular material with a normal coefficient of friction, if the presence of an isotropic dispersive stress within the moving rock debris throughout the runout is assumed. The dispersive stress distribution required to model the rock avalanche runout and match velocities calculated from run-up traces is closely similar to that used to simulate the runout of the much larger Falling Mountain rock avalanche in a similar lithologic and tectonic setting. Both events thus behaved in a fundamentally similar fashion.

The Chernobyl reactor accident in April 1986 released some 3-6.10 5 TBq 137 Cs and 2-4.10 5 TBq 90 Sr to atmosphere. About half of this was deposited within 20 km of the site, leading to extensive death of trees and other biota, and the establishment of a human exclusion zone. High levels of contamination remain in this zone. Nonetheless, birch (Betula spp.) and willow (Salix spp.) have recolonised the forest areas, while abandoned agricultural land has succeeded to tall grassland and scrub. This study summarises observations on invertebrate populations in sites with gamma dose rates varying from 0.1 to 140 µSv h -1 . Corresponding activity concentrations were 3.10 3 to 3.10 6 Bq kg -1 dw 137 Cs and 10 3 to 2.10 6 Bq kg -1 dw 90 Sr in the top 5 cm of soil. Sub-surface bait lamina penetration decreases with increasing concentrations of 137 Cs and 90 Sr in soil. At the highest levels of contamination there is also some loss of above-ground invertebrate diversity; although little change in total biomass. Trials on earthworms in soils from the region and matched soils spiked in the laboratory have proved variable. However, there is a non-significant indication of depressed growth rates in all contaminated regimes compared to control populations.

We have developed and evaluated a CNS-targeted chemotherapy regimen based on the pharmacokinetic properties of the individual drugs in the combination.In a twin-track study, 16 patients with secondary CNS lymphoma (SCNSL) and 8 with primary CNS lymphoma (PCNSL) were treated with IDARAM which comprised idarubicin 10 mg/m(2) i.v., days 1 and 2; dexamethasone 100 mg, 12-h infusion, days 1, 2 and 3; cytosine arabinoside (ARA-C) 1.0 g/m(2), 1-h infusion, days 1 and 2; methotrexate 2.0 g/m(2), 6-h infusion, day 3 (with folinic acid rescue); and cytosine arabinoside 70 mg plus methotrexate 12 mg, intrathecally, days 1 and 8. Two cycles were delivered at 3-weekly intervals. After response assessment, patients received adjuvant cranial radiotherapy (40 Gy over 20 fractions).The series comprised 24 patients, 11 male and 13 female. Their median age was 53 years (range 21 to 73 years). Grade 4 neutropenia and thrombocytopenia occurred in the majority of patients treated. Of the eight PCNSL patients, seven achieved complete remission (CR). Four remained in CR at the time of this report with a median duration of follow-up of 25 months (range 11 to 42 months). Of the 16 SCNSL patients, 12 achieved CR. Seven patients remained in CR at the time of this report with a median duration of follow-up of 24 months (range 18 to 57 months).This study suggests that IDARAM is an effective regimen in both PCNSL and SCNSL and is suitable for further development and evaluation.

Background The aim of this study was to determine in a randomised trial whether there is any significant difference in toxicity between modified CHOP and MCOP chemotherapy in elderly patients with aggressive non-Hodgkin’s lymphoma (NHL) and to determine whether this reduced dose chemotherapy can be administered with full dose intensity, low toxicity and produce acceptable survival. Patients and methods Between 1993 and 2000, 155 eligible patients were randomised into this trial mainly from three centres (Nottingham, Birmingham and Leeds, UK). The patients were newly diagnosed with aggressive NHL and had a median age of 74 years (range 65–91 years). Ninety-six patients (62%) had bulky stage I or II disease; 59 patients (38%) had either stage III or IV disease; 77% had one or more extranodal sites involved at presentation; and 31% showed B symptoms. Seventy-seven patients were randomised to receive six cycles of modified CHOP (cyclophosphamide 600 mg/m2 i.v., doxorubicin 30 mg/m2 i.v., vincristine 1 mg i.v. all on day 1 with prednisolone 20 mg bd for days 1–5) every 21 days and 78 patients to MCOP (mitozantrone 10 mg/m2 i.v. substituted for doxorubicin). Growth factors were not used routinely. After completion of chemotherapy, 39 patients received involved field radiotherapy (35–40 Gy) in 20 fractions. Results One hundred and one patients (65%) completed all six cycles of chemotherapy. The median course dose intensity was 97%. The median follow-up for 53 surviving patients was 51 months. The median survival was 19 months (95% confidence interval 10–36 months) with an actuarial survival of 47% at 2 years and42% at 3 years (CHOP versus MCOP, P = 0.79). There was no significant difference in any of the toxicities experienced with either CHOP or MCOP, except for white cell count (46 patients on MCOP and 27 patients on CHOP had grade 3 or 4 toxicity, P = 0.002) and red cell transfusion (37 patients, MCOP; 17 patients, CHOP; P = 0.001). Grade 3 or 4 neutropenia was documented in 75 patients (50%). One patient died from toxicity whilst in remission and seven patients died with septicaemia and persistent NHL. Conclusion This multicentre randomised trial provides further information on the dose intensity achievable with CHOP or MCOP regimens in elderly patients (median age 74 years) with aggressive NHL. These dose-reduced regimens can be given with nearly 100% dose intensity with 65% of patients completing all the treatment. Survival is comparable to that observed with the more intensive regimens given in this age group.

Objective Aim of the study was determine health care outcomes from the patients' perspective in patients reliant on Mitrofanoff catheterisation for bladder emptying. Subjects/patients Patients over the age of 16 dependent on Mitrofanoff catheterisation for bladder emptying were asked to complete a health care outcome questionnaire, the SF-36 (®) Health Survey v2. Quality of life measures for 8 health concepts were compared against published data for the normal population. Results Out of a total of 25 patients who were eligible for enrolment into our study, we were able to contact 19 patients. The norm-based score for Physical Functioning (PF=50.4), Role Physical (RP=53.8), Bodily Pain (BP=55.6), Vitality (VT=56.9), Social Functioning (SF=51.5), Role Emotional (RE=52.2), and Mental Health (MH=54.6) were all higher than those reported within the normal population (normal=50.0). Physical and mental component summary measures were higher than in the normal population. When compared against age-matched norms our patient group scored higher than the normal population for all measures except Physical Functioning (50.4 vs. 53.4) and physical component summary (51.9 vs. 53.5). The self-reported scores for Vitality, Mental Health and the mental component summary were all statistically significantly better than those seen in the age-matched control population (p Conclusions Quality of life in patients dependent on Mitrofanoff catheterisation for bladder emptying is good. The SF-36 measures 8 major health care outcomes and in our patients these measures of health were similar to those seen in the general population, rather than the poorer outcomes reported in patients with other chronic medical conditions.

Past development of processes and technologies using radioactive material led to construction of many facilities worldwide. Some of these facilities were built and operated before the regulatory infrastructure was in place to ensure adequate control of radioactive material during operation and decommissioning. In other cases, controls were in place but did not meet modern standards, leading to what is now considered to have been inadequate control. Accidents and other events have occurred resulting in loss of control of radioactive material and unplanned releases to the environment. The legacy from these circumstances is that many countries have areas or facilities at which abnormal radiation conditions exist at levels that give rise to concerns about environmental and human health of potential interest to regulatory authorities. Regulation of these legacy situations is complex. This paper examines the regulatory challenges associated with such legacy management and brings forward suggestions for finding the path from: legacy recognition; implementation, as necessary, of urgent mitigation measures; development of a longer-term management strategy, through to release from regulatory control.

Myeloid neoplasms and eosinophilia with rearrangements of PDGFRB are uncommon Philadelphia-negative myeloproliferative neoplasms. Patients are typically male, with morphologic features of a Philadelphia-negative chronic myeloproliferative syndrome or chronic myelomonocytic leukemia with eosinophilia. Reciprocal translocations involving PDGFRB result in fusion genes with constitutively activated receptor tyrosine kinase sensitive to inhibition with imatinib. We present an updated and expanded analysis of a cohort of 26 such patients treated with imatinib. After a median follow-up of 10.2 years (range, 1.8-17 years), the 10-year overall survival rate was 90% (95% confidence interval, 64%-97%); after median imatinib duration of 6.6 years (range, 0.1-12 years), the 6-year progression-free survival rate was 88% (95% confidence interval, 65%-96%). Of the patients, 96% responded; no patients who achieved a complete cytogenetic (n = 13) or molecular (n = 8) remission lost their response or progressed to blast crisis. Imatinib is well-tolerated and achieves excellent long-term responses in patients with PDGFRB rearrangements.

In peripheral blood stem cell transplantation (PBSCT), the number of CD34+ cells transplanted has been shown to correlate well with both rapidity and durability of engraftment. However, it is clear that engraftment does not necessarily correlate with total CD34+ cell numbers in some patients. Consequently, there is increasing interest in evaluating the role of CD34+ subsets in haemopoietic recovery as a more accurate marker of harvest quality. We analysed the numbers of CD34+ cell subsets, namely Thy-1+, L-Selectin+ and CD38-, and correlated this with engraftment in 86 patients undergoing PBSCT. Adequate engraftment was defined as being a platelet count greater than 50 x 10(9)/l and a neutrophil count greater than 1.0 x 10(9)/l. CD34+L-Selectin+ provided the best prediction of engraftment rapidity, although the improvement over total CD34+ cell dose was minor. Only the dose of CD34+Thy-1+ cells transplanted correlated with durable engraftment. The probability of adequate 3-month engraftment increased with the dose of CD34+ cells transplanted, but 10% of patients receiving5 x 10(6)/kg still showed poor engraftment at 3 months. However, all patients receiving2.5 x 10(5)/kg CD34+Thy-1+ showed adequate engraftment at this time point. We also demonstrated that CD34+Thy-1+ progenitors were restricted to the bone marrow under normal conditions and, during stem cell mobilization, their kinetics generally paralleled total CD34+ numbers.

In cycle exercise, it has been suggested that critical power, maximal lactate steady state, and lactate turnpoint all demarcate the transition between the heavy exercise domain (in which blood lactate is elevated above resting values but remains stable over time) and the very heavy exercise domain (in which blood lactate increases continuously throughout constant-intensity exercise). The purpose of the present study was to assess the level of agreement between critical velocity (CV), maximal lactate steady-state velocity (MLSSV), and lactate turnpoint velocity (LTPV) during treadmill running. Eight male subjects [mean (SD) age 28 (5) years, body mass 71.2 (8.0) kg, maximum oxygen uptake 54.9 (3.2) ml.kg(-1).min(-1)) performed an incremental treadmill test for the determination of LTPV (defined as a sudden and sustained increase in blood lactate concentration ([La]) at approximately equals 2.0-5.0 mM). The subjects returned to the laboratory on eight or nine occasions for the determination of CV and MLSSV. The CV was determined from four treadmill runs at velocities that were chosen to result in exhaustion within 2-12 min. The MLSSV was determined from four or five treadmill runs of up to 30 min duration and defined as the highest velocity at which blood [La] increased by no more than 1.0 mM after between 10 and 30 min of exercise. Analysis of variance revealed no significant differences between [mean (SD)] CV [14.4 (1.1) km.h(-1)], MLSSV [13.8 (1.1) km.h(-1)] and LTPV [13.7 (0.6) km.h(-1)]. However, the bias +/-95% limits of agreement for comparisons between CV and MLSSV [0.6 (2.2) km.h(-1)], CV and LTPV [0.7 (2.7) km.h(-1)], and MLSSV and LTPV [0.1 (1.8) km.h(-1)] suggest that the extent of disagreement is too great to allow one variable to be estimated accurately from another in individual subjects. Direct determination of MLSSV is necessary if precision is required in experimental studies.

The majority of patients with multiple myeloma have translocations involving the immunoglobulin heavy chain switch regions on chromosome 14q32 and a promiscuous range of partner chromosomes. We describe a patient with an insertion of 132 bp of chromosome 22q12 sequence into the 5' region flanking S(mu) on chromosome 14q32. The 132 bp region from chromosome 22q12 contains the whole of exon 3 from a novel gene of unknown function in man. The significance of such insertional events remains unclear. The description of insertional events occurring as a result of abnormal switch recombination suggests that, in myeloma, dysregulation of oncogenes may occur by a mechanism other than chromosomal translocation.

A land cover map of Jersey was created using remotely sensed images recorded by satellite. This map brought together a range of disparate techniques, developed in isolation and mostly applied experimentally, integrating multisensor, multitemporal, enhanced spatial resolution data within an object-oriented integrated Geographical Information System (GIS) for an applications-driven, operational programme. It was developed under the Classification of Environment with Vector- and Raster-Mapping (CLEVER-Mapping) project: this improved approach to operational land cover mapping used information on the subdivision of the landscape into land parcels to help classify remotely sensed images on a per-parcel basis. The object-oriented approach allowed the use of remotely sensed information which relates directly to ground features, and the application of improved knowledge-based corrections using a range of external data. Unlike a conventional map, the parcel-based approach produced a GIS database containing classifi...

The primary objective of this study was to determine the complete remission (CR) rate achieved with the FLAG (fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor) regimen in patients with relapsed or refractory acute myeloid leukaemia (AML) or de novo refractory anaemia with excess of blasts in transformation (RAEB-t). Secondary objectives were to evaluate survival and toxicity. Induction treatment consisted of between one and two courses of FLAG. Patients achieving CR received between one and two courses of consolidation treatment. Eighty-three of the 89 patients entering the study were eligible for assessment. CR rates were: 17 out of 21 (81%) in late relapse AML (Group 1), 13 out of 44 (30%) in early relapse/refractory AML (Group 2), and 10 out of 18 (56%) in de novo RAEB-t (Group 3). Thirty-four of the 40 responders (85%) achieved CR after one induction course. Median survival times were 1.4 years, 3 months and 1.6 years in Groups 1, 2 and 3 respectively. Other than myelosuppression, the FLAG regimen was not generally associated with clinically significant toxicity and was well tolerated by most patients including the elderly. The FLAG regimen offers a very effective alternative treatment for CR induction in poor prognosis adult patients with either relapsed or refractory AML or de novo RAEB-t. FLAG delivers high-dose treatment without increasing overall toxicity, an approach which is of particular value in older patients, who constitute the majority in these diseases. It is therefore an important advance in developing new treatment options for these patients.

Neuronal apoptosis inhibitory protein (NAIP), and human inhibitors of apoptosis 1 and 2 (HIAP1 and HIAP2) are three members of the mammalian family of antiapoptosis proteins called ‘inhibitors of apoptosis’ (IAP). These molecules can prevent apoptosis in vitro and the over-expression of NAIP can decrease ischemic damage in the hippocampus. The goal of our experiments was to determine whether administration of NAIP, HIAP1 and HAIP2 could rescue motoneurons following axotomy of a peripheral nerve. In young rats, an adenoviral gene transfer technique was used to deliver and express these proteins in motoneurons; a fluorescent tracer was simultaneously added as a means for quantitatively assessing the rescue of fluorescently labelled motoneurons in serial sections of the lumbar spinal cord. Control experiments using adenoviral vectors (adv) expressing the lacZ gene showed that 14% of the sciatic motoneuron pool could be transfected indicating the existence of a subpopulation of spinal motoneurons susceptible to this class of viral vectors. The administration of an adv-NAIP, adv-HIAP1 and adv-HIAP2 rescued 30–40% of motoneurons at one week after sciatic axotomy. The efficiency of these proteins was similar to that of two neurotrophic factors, ciliary neurotrophic factor and brain-derived neurotrophic factor, administrated by the same viral technique. The effect of the IAP proteins on motoneuron survival decreased with time but was still present after 4 weeks postaxotomy; the duration of the response was dependent upon the viral titre. These experiments demonstrate that IAP family proteins can prevent motoneuron cell death in vivo and may offer a new therapeutic approach for motoneuron diseases.

Recent developments in performance standards for proposed high level radioactive waste disposal at Yucca Mountain suggest that health risk or dose rate limits will likely be part of future standards. Approaches to the development of biosphere modeling and dose assessments for Yucca Mountain have been relatively lacking in previous performance assessments due to the absence of such a requirement. This paper describes a practical methodology used to develop a biosphere model appropriate for calculating doses from use of well water by hypothetical individuals due to discharges of contaminated groundwater into a deep well. The biosphere model methodology, developed in parallel with the BIOMOVS II international study, allows a transparent recording of the decisions at each step, from the specification of the biosphere assessment context through to model development and analysis of results. A list of features, events, and processes relevant to Yucca Mountain was recorded and an interaction matrix developed to help identify relationships between them. Special consideration was given to critical/potential exposure group issues and approaches. The conceptual model of the biosphere system was then developed, based on the interaction matrix, to show how radionuclides migrate and accumulate in the biosphere media and result in potential exposure pathways. A mathematical dose assessment model was specified using the flexible AMBER software application, which allows users to construct their own compartment models. The starting point for the biosphere calculations was a unit flux of each radionuclide from the groundwater in the geosphere into the drinking water in the well. For each of the 26 radionuclides considered, the most significant exposure pathways for hypothetical individuals were identified. For 14 of the radionuclides, the primary exposure pathways were identified as consumption of various crops and animal products following assumed agricultural use of the contaminated water derived from the deep well. Inhalation of dust (11 radionuclides) and external irradiation (1 radionuclide) were also identified as significant exposure modes. Contribution to the total flux to dose conversion factor from the drinking water pathway for each radionuclide was also assessed and for most radionuclides was found to be less than 10% of the total flux to dose conversion factor summed across all pathways. Some of the uncertainties related to the results were considered. The biosphere modeling results have been applied within an EPRI Total Systems Performance Assessment of Yucca Mountain. Conclusions and recommendations for future performance assessments are provided.

The Biospheric Model Validation Study-Phase II (BIOMOVS II) was an international cooperative program that tested the accuracy of predictions of environmental assessment models. Model evaluation was based on calculations made by individual participants for 10 test scenarios that addressed both short- and long-term releases of radioactivity from facilities such as power reactors, solid waste disposal repositories and uranium mill tailings. Model predictions were compared with each other and, where possible, with independent field observations, and reasons were sought for any differences that arose. Qualitative topics were also considered, including development of systematic methodologies for radiological assessments. This paper addresses conclusions arising from the study as a whole. Confidence intervals on predictions and differences between predictions and observations were often less than a factor of 10, although there was much variability among models and scenarios. Model performance depended critically, not only on the formulation and parameter values of the model itself, but also on the experience and assumptions made by the user. The study demonstrated the need to better explain and justify all aspects of model structure and application and to assess all sources of uncertainty. A key recommendation was that assessments should not be undertaken in isolation by one individual using one model.

Liposomal encapsulation of anthracyclines is a potential method of drug targeting, altering both the antitumour activity and side-effect profile of anthracyclines. Liposomal daunorubicin (daunoxome) shows both altered pharmacokinetics and a potential for reducing dose-limiting cardiotoxicity compared to conventional daunorubicin. Anthracyclines have a common role in the treatment of multiple myeloma, a prevalent and fatal haematological malignancy. Avoiding cumulative anthracycline toxicity in these patients is important. There is also a need for more effective relapse schedules given that many patients have chemosensitive disease at relapse. We have analysed daunoxome in vitro in myeloma cell lines using a thymidine-based cytotoxicity assay and show superior efficacy compared to a pegylated liposomal doxorubicin derivative. Subsequently we have treated seven relapsed myeloma patients with a regime consisting of oral CCNU 25–50mg/m2 on day 1, 4 days of oral dexamethasone 10mg/m2 and intravenous daunoxome (liposomal daunorubicin) given for 4 days (total 100mg/m2). The main toxicity was myelosuppression but non-haematological toxicity was minimal and the regime was well tolerated. Four out of seven of these heavily pretreated patients responded. Together with the in vitro data on its cytotoxicity in myeloma and its favourable pharmacokinetic profile further studies of liposomal daunorubicin in myeloma would be warranted. Copyright © 1998 John Wiley & Sons, Ltd.

Autologous transplantation in CML has been a focus of interest over the last few years. Determining the indications, optimal timing and method for this procedure remains controversial. One approach has been the mobilisation of Philadelphia chromosome negative (Ph-) peripheral blood stem cells following high-dose chemotherapy as a method of purging the graft. We have described a mobilisation regimen of 7 days of hydroxyurea followed by G-CSF and have shown it to be substantially less toxic than other methods. We now report further experience with this technique in a total of 18 patients and the outcome of transplantation in seven patients using cells so-derived. Following mobilisation, approximately a third of patients had 100% Ph-collections and half had less than 50% Ph+ collections. All patients were 100% Ph+ prior to mobilisation. Six out of seven transplanted patients showed sustained engraftment and two of these patients became 18 and 34% Ph+ 3 months post-transplant. Five patients remain alive and well 13 to 25 months post-autograft. In conclusion, we have developed a well-tolerated regimen for Ph- PBSC mobilisation and have demonstrated that such cells are capable of sustained engraftment and of producing significant cytogenetic responses.

Purpose This study was performed to investigate the effect of a carbonated beverage on the wear of human enamel and three dental ceramics: a conventional porcelain (Vitadur Alpha), a hydrothermal low-fusing ceramic (Duceram-LFC), and a machinable ceramic (Vita Mark II). Materials and Methods Tooth-against-ceramic specimens (10 per group) were tested in a wear machine under a load of 40N, at a rate of 80 cycles per minute, and for a total of 25,000 cycles. The test was performed in distilled water or with intermittent exposure to a carbonated beverage (Coca-Cola). Wear was determined by measuring the height reduction of the tooth specimens and the depth of wear track in the ceramic specimens. Results ANOVA revealed a significant difference among the groups for both enamel and ceramic wear (p < .001). When tested in water. Alpha porcelain caused significantly more enamel wear and also exhibited greater wear than Duceram-LFC and Vita Mark II. However, with exposure to the carbonated beverage, the enamel wear produced by Duceram-LFC did not differ significantly from that produced by Alpha porcelain, and Vita Mark II produced the least amount of enamel wear. Overall, exposure to the carbonated beverage significantly increased the enamel wear. The wear of Duceram-LFC and Vita Mark II increased with exposure to the carbonated beverage. Conclusions It was concluded that exposure to the carbonated beverage accelerated the enamel wear and decreased the wear resistance of Duceram-LFC and Vita Mark II ceramics. Overall, Vita Mark II was shown to be the most resistant to wear and also significantly less abrasive than conventional Alpha porcelain.

Objectives To examine contemporary survival patterns in the general population of patients diagnosed with chronic myeloid leukaemia (CML), and to identify patient groups with less than optimal outcomes. Design Prospective population-based cohort. Setting The UK9s Haematological Malignancy Research Network (catchment population 3.6 million, with >2000 new haematological malignancies diagnosed annually). Participants All patients newly diagnosed with CML, from September 2004 to August 2011 and followed up to 31 March 2013. Main outcome measure Incidence and survival. Results With a median diagnostic age of 59 years, the CML age standardised (European) incidence was 0.9/100 000 (95% CIs 0.8 to 0.9), 5-year overall survival was 78.9% (72.3 to 84.0) and 5-year relative survival 88.6% (81.0 to 93.3). The efficacy of treatment across all ages was clearly demonstrated; the relative survival curves for those under 60 and over 60 years being closely aligned. Survival findings were similar for men and women, but varied with deprivation; the age and sex adjusted HR being 3.43 (1.89 to 6.22) for deprivation categories 4–5 (less affluent) versus 1–3 (more affluent). None of these differences were attributable to the biological features of the disease. Conclusions When therapy is freely provided, population-based survival for CML is similar to that reported in clinical trials, and age loses its prognostic significance. However, although most of the patients with CML now experience close to normal lifespans, those living in more deprived areas tend to have poorer outcomes, despite receiving the same clinical care. A significant improvement in overall population outcomes could be achieved if these socioeconomic differences, which may reflect the treatment compliance, could be eliminated.