Management of patients with multiple myeloma beyond the clinical-trial setting: understanding the balance between efficacy, safety and tolerability, and quality of life.

Treatment options in multiple myeloma (MM) are increasing with the introduction of complex multi-novel-agent-based regimens investigated in randomized clinical trials. However, application in the real-world setting, including feasibility of and adherence to these regimens, may be limited due to varying patient-, treatment-, and disease-related factors. Furthermore, approximately 40% of real-world MM patients do not meet the criteria for phase 3 studies on which approvals are based, resulting in a lack of representative phase 3 data for these patients. Therefore, treatment decisions must be tailored based on additional considerations beyond clinical trial efficacy and safety, such as treatment feasibility (including frequency of clinic/hospital attendance), tolerability, effects on quality of life (QoL), and impact of comorbidities. There are multiple factors of importance to real-world MM patients, including disease symptoms, treatment burden and toxicities, ability to participate in daily activities, financial burden, access to treatment and treatment centers, and convenience of treatment. All of these factors are drivers of QoL and treatment satisfaction/compliance. Importantly, given the heterogeneity of MM, individual patients may have different perspectives regarding the most relevant considerations and goals of their treatment. Patient perspectives/goals may also change as they move through their treatment course. Thus, the 'efficacy' of treatment means different things to different patients, and treatment decision-making in the context of personalized medicine must be guided by an individual's composite definition of what constitutes the best treatment choice. This review summarizes the various factors of importance and practical issues that must be considered when determining real-world treatment choices. It assesses the current instruments, methodologies, and recent initiatives for analyzing the MM patient experience. Finally, it suggests options for enhancing data collection on patients and treatments to provide a more holistic definition of the effectiveness of a regimen in the real-world setting.

The role of ixazomib as an augmented conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT consolidation and maintenance strategy in patients with relapsed multiple myeloma (ACCoRd [UK-MRA Myeloma XII] trial): study protocol for a Phase III randomised controlled trial.

BACKGROUND: Multiple myeloma (MM) is a plasma cell tumour with an approximate annual incidence of 4500 in the UK. Therapeutic options for patients with MM have changed in the last decade with the arrival of proteasome inhibitors and immunomodulatory drugs. Despite these options, almost all patients will relapse post first-line autologous stem cell transplantation (ASCT). First relapse management (second-line treatment) has evolved in recent years with an expanding portfolio of novel agents, driving response rates influencing the durability of response. A second ASCT, as part of relapsed disease management (salvage ASCT), has been shown to prolong the progression-free survival and overall survival following a proteasome inhibitor-containing re-induction regimen, in the Cancer Research UK-funded National Cancer Research Institute Myeloma X (Intensive) study. It is now recommended that salvage ASCT be considered for suitable patients by the International Myeloma Working Group and the National Institute for Health and Care Excellence NG35 guidance. METHODS/DESIGN: ACCoRd (Myeloma XII) is a UK-nationwide, individually randomised, multi-centre, multiple randomisation, open-label phase III trial with an initial single intervention registration phase aimed at relapsing MM patients who have received ASCT in first-line treatment. We will register 406 participants into the trial to allow 284 and 248 participants to be randomised at the first and second randomisations, respectively. All participants will receive re-induction therapy until maximal response (four to six cycles of ixazomib, thalidomide and dexamethasone). Participants who achieve at least stable disease will be randomised (1:1) to receive either ASCTCon, using high-dose melphalan, or ASCTAug, using high-dose melphalan with ixazomib. All participants achieving or maintaining a minimal response or better, following salvage ASCT, will undergo a second randomisation (1:1) to consolidation and maintenance or observation. Participants randomised to consolidation and maintenance will receive consolidation with two cycles of ixazomib, thalidomide and dexamethasone, and maintenance with ixazomib until disease progression. DISCUSSION: The question of how best to maximise the durability of response to salvage ASCT warrants clinical investigation. Given the expanding scope of oral therapeutic agents, patient engagement with long-term maintenance strategies is a real opportunity. This study will provide evidence to better define post-relapse treatment in MM. TRIAL REGISTRATION: ISRCTN, ISRCTN10038996 . Registered on 15 December 2016.

The Beaker phenomenon and the genomic transformation of northwest Europe.

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain's gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries.

Determination of chlorpropham (CIPC) residues, in the concrete flooring of potato stores, using quantitative (HPLC UV/VIS) and qualitative (GCMS) methods.

Isopropyl-N-(3-chlorophenyl) carbamate (CIPC, common name Chlorpropham) is commonly used for post-harvest sprout inhibition in stored potatoes. It is applied as a thermal fog which results in loss to the fabric of the store and the atmosphere. Recently, there have been concerns in the United Kingdom because of cross contamination of other crop commodities that were stored in buildings with a history of CIPC usage. This cross contamination may have occurred because of retained residues in the fabric of the stores. The retention of CIPC in concrete is poorly understood; therefore the requirement for a robust analytical method for the detection and quantification of CIPC in concrete is a critical first step in tackling this problem. A method using High-Performance Liquid Chromatography with ultraviolet detection (HPLC UV/VIS) was validated. CIPC recoveries at three concentration levels (0.4, 4.0 and 40.0 µg g-1) were in the range of 90.7-97.0% with relative standard deviations between 2.14 and 3.01%. The limits of detection and quantification were 0.03 and 0.1 µg g-1, respectively. This study confirmed that CIPC was persistent in concrete to a depth of 4 cm, with >90% within the top 1 cm of the flooring.

Land use and mobility during the Neolithic in Wales explored using isotope analysis of tooth enamel.

OBJECTIVES: The nature of land use and mobility during the transition to agriculture has often been debated. Here, we use isotope analysis of tooth enamel from human populations buried in two different Neolithic burial monuments, Penywyrlod and Ty Isaf, in south-east Wales, to examine patterns of land use and to evaluate where individuals obtained their childhood diet. MATERIALS AND METHODS: We employ strontium (87 Sr/86 Sr) and oxygen (δ18 O) and carbon (δ13 C) isotope analysis of enamel from adjacent molars. We compare strontium isotope values measured in enamel to locally bioavailable 87 Sr/86 Sr values. We combine discussion of these results with evaluation of new radiocarbon dates obtained from both sites. RESULTS: The majority of enamel samples from Penywyrlod have strontium isotope ratios above 0.7140. In contrast, the majority of those from Ty Isaf have 87 Sr/86 Sr values below 0.7140. At Penywyrlod oxygen isotope ratios range between 25.9 and 28.2 ‰ (mean 26.7 ± 0.6 ‰, 1σ, n = 15) and enamel δ13 Ccarbonate values range between -18.0 and -15.0 ‰ (mean -16.0 ± 0.8 ‰, 1σ, n = 15). At Ty Isaf oxygen isotope ratios exhibited by Neolithic individuals range between 25.4 and 27.7 ‰ (mean 26.7 ± 0.6 ‰, 1σ, n = 15) and enamel δ13 Ccarbonate values range between -16.9 and -14.9 ‰ (mean -16.0 ± 0.6 ‰, 1σ, n = 15). DISCUSSION: The strontium isotope results suggest that the majority of individuals buried at Penywyrlod did not source their childhood diet locally. One individual in this group has strontium isotope ratios that exceed all current known biosphere values within England and Wales. This individual is radiocarbon dated to the first few centuries of the 4th millennium BC, consistent with the period in which agriculture was initiated in Wales: the results therefore provide evidence for migration during the transition to farming in Wales. In contrast, all individuals sampled from Ty Isaf post-date the period in which agriculture is considered to have been initiated and could have sourced their childhood diet from the local region in which they were buried.

Deciphering diet and monitoring movement: Multiple stable isotope analysis of the viking age settlement at Hofstaðir, Lake Mývatn, Iceland.

OBJECTIVES: A previous multi-isotope study of archaeological faunal samples from Skútustaðir, an early Viking age settlement on the southern shores of Lake Mývatn in north-east Iceland, demonstrated that there are clear differences in δ(34)S stable isotope values between animals deriving their dietary protein from terrestrial, freshwater, and marine reservoirs. The aim of this study was to use this information to more accurately determine the diet of humans excavated from a nearby late Viking age churchyard. MATERIALS AND METHODS: δ(13)C, δ(15)N, and δ(34)S analyses were undertaken on terrestrial animal (n = 39) and human (n = 46) bone collagen from Hofstaðir, a high-status Viking-period farmstead ∼10 km north-west of Skútustaðir. RESULTS: δ(34)S values for Hofstaðir herbivores were ∼6‰ higher relative to those from Skútustaðir (δ(34)S: 11.4 ± 2.3‰ versus 5.6 ± 2.8‰), while human δ(13)C, δ(15)N, and δ(34)S values were broad ranging (-20.2‰ to -17.3‰, 7.4‰ to 12.3‰, and 5.5‰ to 14.9‰, respectively). DISCUSSION: Results suggest that the baseline δ(34)S value for the Mývatn region is higher than previously predicted due to a possible sea-spray effect, but the massive deposition of Tanytarsus gracilentus (midges) (δ(34)S: -3.9‰) in the soil in the immediate vicinity of the lake is potentially lowering this value. Several terrestrial herbivores displayed higher bone collagen δ(34)S values than their contemporaries, suggesting trade and/or movement of animals to the region from coastal areas. Broad ranging δ(13)C, δ(15)N, and δ(34)S values for humans suggest the population were consuming varied diets, while outliers within the dataset could conceivably have been migrants to the area.

Radioactive isotope analyses of skeletal materials in forensic science: a review of uses and potential uses.

A review of information that can be provided from measurements made on natural and anthropogenic radionuclide activities in human skeletal remains has been undertaken to establish what reliable information of forensic anthropological use can be obtained regarding years of birth and death (and hence post-mortem interval (PMI)). Of the anthropogenic radionuclides that have entered the environment, radiocarbon ((14)C) can currently be used to generate the most useful and reliable information. Measurements on single bones can indicate whether or not the person died during the nuclear era, while recent research suggests that measurements on trabecular bone may, depending on the chronological age of the remains, provide estimates of year of death and hence PMI. Additionally, (14)C measurements made on different components of single teeth or on teeth formed at different times can provide estimates of year of birth to within 1-2 years of the true year. Of the other anthropogenic radionuclides, (90)Sr shows some promise but there are problems of (1) variations in activities between individuals, (2) relatively large analytical uncertainties and (3) diagenetic contamination. With respect to natural series radionuclides, it is concluded that there is no convincing evidence that (210)Pb dating can be used in a rigorous, quantitative fashion to establish a PMI. Similarly, for daughter/parent pairs such as (210)Po/(210)Pb (from the (238)U decay series) and (228)Th/(228)Ra (from the (232)Th decay series), the combination of analytical uncertainty and uncertainty in activity ratios at the point of death inevitably results in major uncertainty in any estimate of PMI. However, observation of the disequilibrium between these two daughter/parent pairs could potentially be used in a qualitative way to support other forensic evidence.

Historical accumulation rates of mercury in four Scottish ombrotrophic peat bogs over the past 2000 years.

The historical accumulation rates of mercury resulting from atmospheric deposition to four Scottish ombrotrophic peat bogs, Turclossie Moss (northeast Scotland), Flanders Moss (west-central), Red Moss of Balerno (east-central) and Carsegowan Moss (southwest), were determined via analysis of (210)Pb- and (14)C-dated cores up to 2000 years old. Average pre-industrial rates of mercury accumulation of 4.5 and 3.7 microg m(-2) y(-1) were obtained for Flanders Moss (A.D. 1-1800) and Red Moss of Balerno (A.D. 800-1800), respectively. Thereafter, mercury accumulation rates increased to typical maximum values of 51, 61, 77 and 85 microg m(-2) y(-1), recorded at different times possibly reflecting local/regional influences during the first 70 years of the 20th century, at the four sites (TM, FM, RM, CM), before declining to a mean value of 27+/-15 microg m(-2) y(-1) during the late 1990s/early 2000s. Comparison of such trends for mercury with those for lead and arsenic in the cores and also with direct data for the declining UK emissions of these three elements since 1970 suggested that a substantial proportion of the mercury deposited at these sites over the past few decades originated from outwith the UK, with contributions to wet and dry deposition arising from long-range transport of mercury released by sources such as combustion of coal. Confidence in the chronological reliability of these core-derived trends in absolute and relative accumulation of mercury, at least since the 19th century, was provided by the excellent agreement between the corresponding detailed and characteristic temporal trends in the (206)Pb/(207)Pb isotopic ratio of lead in the (210)Pb-dated Turclossie Moss core and those in archival Scottish Sphagnum moss samples of known date of collection. The possibility of some longer-term loss of volatile mercury released from diagenetically altered older peat cannot, however, be excluded by the findings of this study.

A comparison of antimony and lead profiles over the past 2500 years in Flanders Moss ombrotrophic peat bog, Scotland.

Two cores collected in 2001 and 2004 from Flanders Moss ombrotrophic peat bog in central Scotland were dated (14C, 210Pb) and analysed (ICP-OES, ICP-MS) to derive and compare the historical atmospheric deposition records of Sb and Pb over the past 2500 years. After correction, via Sc, for contributions from soil dust, depositional fluxes of Sb and Pb peaked from ca. 1920-1960 A.D., with >95% of the anthropogenic inventories deposited post-1800 A.D. Over the past two centuries, trends in Sb and Pb deposition have been broadly similar, with fluctuations in the anthropogenic Sb/Pb ratio reflecting temporal variations in the relative input from emission sources such as the mining and smelting of Pb ores (in which Sb is commonly present, as at Leadhills/Wanlockhead in southern Scotland), combustion of coal (for which the Sb/Pb ratio is approximately an order of magnitude greater than in Pb ores) and exhaust emissions (Pb from leaded petrol) and abrasion products from the brake linings (Sb from heat-resistant Sb compounds) of automobiles. The influence of leaded petrol has been most noticeable in recent decades, firstly through the resultant minima in Sb/Pb and 206Pb/207Pb ratios (the latter arising from the use of less radiogenic Australian Pb in alkylPb additives) and then, during its phasing out and the adoption of unleaded petrol, complete by 2000 A.D., the subsequent increase in both Sb/Pb and 206Pb/207Pb ratios. The extent of the 20th century maximum anthropogenic enrichment of Sb and Pb, relative to the natural Sc-normalised levels of the Upper Continental Crust, was similar at approximately 50- to 100-fold. Prior to 1800 A.D., the influence of metallurgical activities on Sb and Pb concentrations in the peat cores during both the Mediaeval and Roman/pre-Roman periods was discernible, small Sb and Pb peaks during the latter appearing attributable, on the basis of Pb isotopic composition, to the mining/smelting of Pb ores indigenous to Britain.