Endometrial scratch to increase live birth rates in women undergoing first-time in vitro fertilisation: RCT and systematic review.

BACKGROUND: In vitro fertilisation is a widely used reproductive technique that can be undertaken with or without intracytoplasmic sperm injection. The endometrial scratch procedure is an in vitro fertilisation 'add-on' that is sometimes provided prior to the first in vitro fertilisation cycle, but there is a lack of evidence to support its use. OBJECTIVES: (1) To assess the clinical effectiveness, safety and cost-effectiveness of endometrial scratch compared with treatment as usual in women undergoing their first in vitro fertilisation cycle (the 'Endometrial Scratch Trial') and (2) to undertake a systematic review to combine the results of the Endometrial Scratch Trial with those of previous trials in which endometrial scratch was provided prior to the first in vitro fertilisation cycle. DESIGN: A pragmatic, multicentre, superiority, open-label, parallel-group, individually randomised controlled trial. Participants were randomised (1 : 1) via a web-based system to receive endometrial scratch or treatment as usual using stratified block randomisation. The systematic review involved searching electronic databases (undertaken in January 2020) and clinicaltrials.gov (undertaken in September 2020) for relevant trials. SETTING: Sixteen UK fertility units. PARTICIPANTS: Women aged 18-37 years, inclusive, undergoing their first in vitro fertilisation cycle. The exclusion criteria included severe endometriosis, body mass index ≥ 35 kg/m2 and previous trauma to the endometrium. INTERVENTIONS: Endometrial scratch was undertaken in the mid-luteal phase of the menstrual cycle prior to in vitro fertilisation, and involved inserting a pipelle into the cavity of the uterus and rotating and withdrawing it three or four times. The endometrial scratch group then received usual in vitro fertilisation treatment. The treatment-as-usual group received usual in vitro fertilisation only. MAIN OUTCOME MEASURES: The primary outcome was live birth after completion of 24 weeks' gestation within 10.5 months of egg collection. Secondary outcomes included implantation, pregnancy, ectopic pregnancy, miscarriage, pain and tolerability of the procedure, adverse events and treatment costs. RESULTS: One thousand and forty-eight (30.3%) women were randomised to treatment as usual (n = 525) or endometrial scratch (n = 523) and were followed up between July 2016 and October 2019 and included in the intention-to-treat analysis. In the endometrial scratch group, 453 (86.6%) women received the endometrial scratch procedure. A total of 494 (94.1%) women in the treatment-as-usual group and 497 (95.0%) women in the endometrial scratch group underwent in vitro fertilisation. The live birth rate was 37.1% (195/525) in the treatment-as-usual group and 38.6% (202/523) in the endometrial scratch group: an unadjusted absolute difference of 1.5% (95% confidence interval -4.4% to 7.4%; p = 0.621). There were no statistically significant differences in secondary outcomes. Safety events were comparable across groups. No neonatal deaths were recorded. The cost per successful live birth was £11.90 per woman (95% confidence interval -£134 to £127). The pooled results of this trial and of eight similar trials found no evidence of a significant effect of endometrial scratch in increasing live birth rate (odds ratio 1.03, 95% confidence interval 0.87 to 1.22). LIMITATIONS: A sham endometrial scratch procedure was not undertaken, but it is unlikely that doing so would have influenced the results, as objective fertility outcomes were used. A total of 9.2% of women randomised to receive endometrial scratch did not undergo the procedure, which may have slightly diluted the treatment effect. CONCLUSIONS: We found no evidence to support the theory that performing endometrial scratch in the mid-luteal phase in women undergoing their first in vitro fertilisation cycle significantly improves live birth rate, although the procedure was well tolerated and safe. We recommend that endometrial scratch is not undertaken in this population. TRIAL REGISTRATION: This trial is registered as ISRCTN23800982. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 10. See the NIHR Journals Library website for further project information.

The endometrial scratch is a simple procedure that involves 'scratching' the lining of the womb (the endometrium). Several small studies have shown that undertaking this before the first in vitro fertilisation cycle may improve live birth rates; however, other studies have contradicted this. This large study was carried out to confirm whether or not having an endometrial scratch before the first in vitro fertilisation cycle would increase the number of women having a live birth compared with those having 'usual' in vitro fertilisation treatment (known as the 'control' group). We collected information about pregnancy, miscarriage, stillbirth, pain during the procedure and costs of treatment to find out if there were any meaningful differences. A total of 1048 women aged between 18 and 37 years were randomly allocated to the two groups, so participants had a 50% chance of having the endometrial scratch. Women were followed up throughout their pregnancy to ascertain the outcome of their in vitro fertilisation cycle. Although the live birth rate was 1.5% higher in the endometrial scratch group (38.6%) than in the control group (37.1%), the difference was not large enough to show any benefit of having the procedure. Other outcomes did not differ significantly between the two groups. However, the procedure was safe and tolerable. We found that the cost of treatment was, on average, £316 per participant higher in the group that received endometrial scratch than in the control group; the difference was not large enough to show that receiving endometrial scratch was more cost-effective. We combined the results of this trial with those of previous trials that looked to answer a similar question, and found that, overall, the endometrial scratch procedure does not enhance the chances of achieving a live birth. We conclude that endometrial scratch before first-time in vitro fertilisation does not improve the outcome of treatment, and we recommend that this procedure is not undertaken prior to a first cycle of in vitro fertilisation.

The Importance of Accounting for Parameter Uncertainty in SF-6D Value Sets and Its Impact on Studies that Use the SF-6D to Measure Health Utility.

BACKGROUND: The parameter uncertainty in the six-dimensional health state short form (SF-6D) value sets is commonly ignored. There are two sources of parameter uncertainty: uncertainty around the estimated regression coefficients and uncertainty around the model's specification. This study explores these two sources of parameter uncertainty in the value sets using probabilistic sensitivity analysis (PSA) and a Bayesian approach. METHODS: We used data from the original UK/SF-6D valuation study to evaluate the extent of parameter uncertainty in the value set. First, we re-estimated the Brazier model to replicate the published estimated coefficients. Second, we estimated standard errors around the predicted utility of each SF-6D state to assess the impact of parameter uncertainty on these estimated utilities. Third, we used Monte Carlo simulation technique to account for the uncertainty on these estimates. Finally, we used a Bayesian approach to quantifying parameter uncertainty in the value sets. The extent of parameter uncertainty in SF-6D value sets was assessed using data from the Hong Kong valuation study. RESULTS: Including parameter uncertainty results in wider confidence/credible intervals and improved coverage probability using both approaches. Using PSA, the mean 95% confidence intervals widths for the mean utilities were 0.1394 (range: 0.0565-0.2239) and 0.0989 (0.0048-0.1252) with and without parameter uncertainty whilst, using the Bayesian approach, this was 0.1478 (0.053-0.1665). Upon evaluating the impact of parameter uncertainty on estimates of a population's mean utility, the true standard error was underestimated by 79.1% (PSA) and 86.15% (Bayesian) when parameter uncertainty was ignored. CONCLUSIONS: Parameter uncertainty around the SF-6D value set has a large impact on the predicted utilities and estimated confidence intervals. This uncertainty should be accounted for when using SF-6D utilities in economic evaluations. Ignoring this additional information could impact misleadingly on policy decisions.

Induced endometrial trauma (endometrial scratch) in the mid-luteal menstrual cycle phase preceding first cycle IVF/ICSI versus usual IVF/ICSI therapy: study protocol for a randomised controlled trial.

INTRODUCTION: Endometrial trauma commonly known as endometrial scratch (ES) has been shown to improve pregnancy rates in women with a history of repeated implantation failure undergoing in vitro fertilisation (IVF), with or without intracytoplasmic sperm injection (ICSI). However, the procedure has not yet been fully explored in women having IVF/ICSI for the first time. This study aims to examine the effect of performing an ES in the mid-luteal phase prior to a first-time IVF/ICSI cycle on the chances of achieving a clinical pregnancy and live birth. If ES can influence this success rate, there would be a significant cost saving to the National Health Service through decreasing the number of IVF/ICSI cycles necessary to achieve a pregnancy, increase the practice of single embryo transfer and consequently have a large impact on risks and costs associated with multiple pregnancies. METHODS AND ANALYSIS: This 30-month, UK, multicentre, parallel group, randomised controlled trial includes a 9-month internal pilot and health economic analysis recruiting 1044 women from 16 fertility units. It will follow up participants to identify if IVF/ICSI has been successful and live birth has occurred up to 6 weeks post partum. Primary analysis will be on an intention-to-treat basis. A substudy of endometrial samples obtained during the ES will assess the role of immune factors in embryo implantation. Main trial recruitment commenced on January 2017 and is ongoing.Participants randomised to the intervention group will receive the ES procedure in the mid-luteal phase of the preceding cycle prior to first-time IVF/ICSI treatment versus usual IVF/ICSI treatment in the control group, with 1:1 randomisation. The primary outcome is live birth rate after completed 24 weeks gestation. ETHICS AND DISSEMINATION: South Central-Berkshire Research Ethics Committee approved the protocol. Findings will be submitted to peer-reviewed journals and abstracts to relevant national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN23800982; Pre-results.

Australian Utility Weights for the EORTC QLU-C10D, a Multi-Attribute Utility Instrument Derived from the Cancer-Specific Quality of Life Questionnaire, EORTC QLQ-C30.

BACKGROUND: The EORTC QLU-C10D is a new multi-attribute utility instrument derived from the widely used cancer-specific quality-of-life (QOL) questionnaire, EORTC QLQ-C30. The QLU-C10D contains ten dimensions (Physical, Role, Social and Emotional Functioning; Pain, Fatigue, Sleep, Appetite, Nausea, Bowel Problems), each with four levels. To be used in cost-utility analysis, country-specific valuation sets are required. OBJECTIVE: The aim of this study was to provide Australian utility weights for the QLU-C10D. METHODS: An Australian online panel was quota-sampled to ensure population representativeness by sex and age (≥ 18 years). Participants completed a discrete choice experiment (DCE) consisting of 16 choice-pairs. Each pair comprised two QLU-C10D health states plus life expectancy. Data were analysed using conditional logistic regression, parameterised to fit the quality-adjusted life-year framework. Utility weights were calculated as the ratio of each QOL dimension-level coefficient to the coefficient on life expectancy. RESULTS: A total of 1979 panel members opted in, 1904 (96%) completed at least one choice-pair, and 1846 (93%) completed all 16 choice-pairs. Dimension weights were generally monotonic: poorer levels within each dimension were generally associated with greater utility decrements. The dimensions that impacted most on choice were, in order, Physical Functioning, Pain, Role Functioning and Emotional Functioning. Oncology-relevant dimensions with moderate impact were Nausea and Bowel Problems. Fatigue, Trouble Sleeping and Appetite had relatively small impact. The value of the worst health state was -0.096, somewhat worse than death. CONCLUSIONS: This study provides the first country-specific value set for the QLU-C10D, which can facilitate cost-utility analyses when applied to data collected with the EORTC QLQ-C30, prospectively and retrospectively.

Randomized trial finds that prostate cancer genetic risk score feedback targets prostate-specific antigen screening among at-risk men.

BACKGROUND: Prostate-specific antigen (PSA) screening may reduce death due to prostate cancer but leads to the overdiagnosis of many cases of indolent cancer. Targeted use of PSA screening may reduce overdiagnosis. Multimarker genomic testing shows promise for risk assessment and could be used to target PSA screening. METHODS: To test whether counseling based on the family history (FH) and counseling based on a genetic risk score (GRS) plus FH would differentially affect subsequent PSA screening at 3 months (primary outcome), a randomized trial of FH versus GRS plus FH was conducted with 700 whites aged 40 to 49 years without prior PSA screening. Secondary outcomes included anxiety, recall, physician discussion at 3 months, and PSA screening at 3 years. Pictographs versus numeric presentations of genetic risk were also evaluated. RESULTS: At 3 months, no significant differences were observed in the rates of PSA screening between the FH arm (2.1%) and the GRS-FH arm (4.5% with GRS-FH vs. 2.1% with FH: χ2 = 3.13, P = .077); however, PSA screening rates at 3 months significantly increased with given risk in the GRS-FH arm (P = .013). Similar results were observed for discussions with physicians at 3 months and PSA screening at 3 years. Average anxiety levels decreased after the individual cancer risk was provided (P = .0007), with no differences between groups. Visual presentation by pictographs did not significantly alter comprehension or anxiety. CONCLUSIONS: This is likely the first randomized trial of multimarker genomic testing to report genomic targeting of cancer screening. This study found little evidence of concern about excess anxiety or overuse/underuse of PSA screening when multimarker genetic risks were provided to patients. Cancer 2016;122:3564-3575. © 2016 American Cancer Society.

Deriving a Preference-Based Measure for Myelofibrosis from the EORTC QLQ-C30 and the MF-SAF.

BACKGROUND: Utility values are required for economic evaluation using cost-utility analyses. Often, generic measures such as the EuroQol five-dimensional questionnaire are used, but this may not appropriately reflect the health-related quality of life of patients with cancer including myelofibrosis. OBJECTIVE: To derive a condition-specific preference-based measure for myelofibrosis using appropriate existing measures, the Myelofibrosis-Symptom Assessment Form and the European Organisation for Research and Treatment of Cancer Quality of Life 30 Questionnaire. METHODS: Data from the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment trial (n = 309) were used to derive the health state classification system. Psychometric and factor analyses were used to determine the dimensions of the classification system. Psychometric and Rasch analyses were then used to select an item to represent each dimension. Item selection was validated with experts. A selection of health states was valued by members of the general population using time trade-off. Finally, health state values were modeled using regression analysis to produce utility values for every state. RESULTS: The Myelofibrosis 8 dimensions has eight dimensions: physical functioning, emotional functioning, fatigue, itchiness, pain under ribs on the left side, abdominal discomfort, bone or muscle pain, and night sweats. Regression models were estimated using time trade-off data from 246 members of the general population valuing a total of 33 states. The best performing model was a random effects maximum likelihood model producing utility values ranging from 0.089 to 1. CONCLUSIONS: The Myelofibrosis 8 dimensions is a condition-specific preference-based measure for myelofibrosis. This measure can be used to generate utility values for myelofibrosis for any data set containing the Myelofibrosis-Symptom Assessment Form and the European Organisation for Research and Treatment of Cancer Quality of Life 30 Questionnaire data.

Mapping Functions in Health-Related Quality of Life: Mapping from Two Cancer-Specific Health-Related Quality-of-Life Instruments to EQ-5D-3L.

BACKGROUND: Clinical trials in cancer frequently include cancer-specific measures of health but not preference-based measures such as the EQ-5D that are suitable for economic evaluation. Mapping functions have been developed to predict EQ-5D values from these measures, but there is considerable uncertainty about the most appropriate model to use, and many existing models are poor at predicting EQ-5D values. This study aims to investigate a range of potential models to develop mapping functions from 2 widely used cancer-specific measures (FACT-G and EORTC-QLQ-C30) and to identify the best model. METHODS: Mapping models are fitted to predict EQ-5D-3L values using ordinary least squares (OLS), tobit, 2-part models, splining, and to EQ-5D item-level responses using response mapping from the FACT-G and QLQ-C30. A variety of model specifications are estimated. Model performance and predictive ability are compared. Analysis is based on 530 patients with various cancers for the FACT-G and 771 patients with multiple myeloma, breast cancer, and lung cancer for the QLQ-C30. RESULTS: For FACT-G, OLS models most accurately predict mean EQ-5D values with the best predicting model using FACT-G items with similar results using tobit. Response mapping has low predictive ability. In contrast, for the QLQ-C30, response mapping has the most accurate predictions using QLQ-C30 dimensions. The QLQ-C30 has better predicted EQ-5D values across the range of possible values; however, few respondents in the FACT-G data set have low EQ-5D values, which reduces the accuracy at the severe end. CONCLUSIONS: OLS and tobit mapping functions perform well for both instruments. Response mapping gives the best model predictions for QLQ-C30. The generalizability of the FACT-G mapping function is limited to populations in moderate to good health.

Deriving a preference-based utility measure for cancer patients from the European Organisation for the Research and Treatment of Cancer's Quality of Life Questionnaire C30: a confirmatory versus exploratory approach.

BACKGROUND: Multi attribute utility instruments (MAUIs) are preference-based measures that comprise a health state classification system (HSCS) and a scoring algorithm that assigns a utility value to each health state in the HSCS. When developing a MAUI from a health-related quality of life (HRQOL) questionnaire, first a HSCS must be derived. This typically involves selecting a subset of domains and items because HRQOL questionnaires typically have too many items to be amendable to the valuation task required to develop the scoring algorithm for a MAUI. Currently, exploratory factor analysis (EFA) followed by Rasch analysis is recommended for deriving a MAUI from a HRQOL measure. AIM: To determine whether confirmatory factor analysis (CFA) is more appropriate and efficient than EFA to derive a HSCS from the European Organisation for the Research and Treatment of Cancer's core HRQOL questionnaire, Quality of Life Questionnaire (QLQ-C30), given its well-established domain structure. METHODS: QLQ-C30 (Version 3) data were collected from 356 patients receiving palliative radiotherapy for recurrent/metastatic cancer (various primary sites). The dimensional structure of the QLQ-C30 was tested with EFA and CFA, the latter informed by the established QLQ-C30 structure and views of both patients and clinicians on which are the most relevant items. Dimensions determined by EFA or CFA were then subjected to Rasch analysis. RESULTS: CFA results generally supported the proposed QLQ-C30 structure (comparative fit index =0.99, Tucker-Lewis index =0.99, root mean square error of approximation =0.04). EFA revealed fewer factors and some items cross-loaded on multiple factors. Further assessment of dimensionality with Rasch analysis allowed better alignment of the EFA dimensions with those detected by CFA. CONCLUSION: CFA was more appropriate and efficient than EFA in producing clinically interpretable results for the HSCS for a proposed new cancer-specific MAUI. Our findings suggest that CFA should be recommended generally when deriving a preference-based measure from a HRQOL measure that has an established domain structure.

Use of generic and condition-specific measures of health-related quality of life in NICE decision-making: a systematic review, statistical modelling and survey.

BACKGROUND: The National Institute for Health and Care Excellence recommends the use of generic preference-based measures (GPBMs) of health for its Health Technology Assessments (HTAs). However, these data may not be available or appropriate for all health conditions. OBJECTIVES: To determine whether GPBMs are appropriate for some key conditions and to explore alternative methods of utility estimation when data from GPBMs are unavailable or inappropriate. DESIGN: The project was conducted in three stages: (1) A systematic review of the psychometric properties of three commonly used GPBMs [EQ-5D, SF-6D and Health Utilities Index Mark 3 (HUI3)] in four broadly defined conditions: visual impairment, hearing impairment, cancer and skin conditions. (2) Potential modelling approaches to 'map' EQ-5D values from condition-specific and clinical measures of health [European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and Functional Assessment of Cancer Therapy - General Scale (FACT-G)] are compared for predictive ability and goodness of fit using two separate data sets. (3) Three potential extensions to the EQ-5D are developed as 'bolt-on' items relating to hearing, tiredness and vision. They are valued using the time trade-off method. A second valuation study is conducted to fully value the EQ-5D with and without the vision bolt-on item in an additional sample of 300 people. SETTING: The valuation surveys were conducted using face-to-face interviews in the respondents' homes. PARTICIPANTS: Two representative samples of the UK general population from Yorkshire (n=600). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Comparisons of EQ-5D, SF-6D and HUI3 in four conditions with various generic and condition-specific measures. Mapping functions were estimated between EORTC QLQ-C30 and FACT-G with EQ-5D. Three bolt-ons to the EQ-5D were developed: EQ + hearing/vision/tiredness. A full valuation study was conducted for the EQ + vision. RESULTS: (1) EQ-5D was valid and responsive for skin conditions and most cancers; in vision, its performance varied according to aetiology; and performance was poor for hearing impairments. The HUI3 performed well for hearing and vision disorders. It also performed well in cancers although evidence was limited and there was no evidence in skin conditions. There were limited data for SF-6D in all four conditions and limited evidence on reliability of all instruments. (2) Mapping algorithms were estimated to predict EQ-5D values from alternative cancer-specific measures of health. Response mapping using all the domain scores was the best performing model for the EORTC QLQ-C30. In an exploratory analysis, a limited dependent variable mixture model performed better than an equivalent linear model. In the full analysis for the FACT-G, linear regression using ordinary least squares gave the best predictions followed by the tobit model. (3) The exploratory valuation study found that bolt-on items for vision, hearing and tiredness had a significant impact on values of the health states, but the direction and magnitude of differences depended on the severity of the health state. The vision bolt-on item had a statistically significant impact on EQ-5D health state values and a full valuation model was estimated. CONCLUSIONS: EQ-5D performs well in studies of cancer and skin conditions. Mapping techniques provide a solution to predict EQ-5D values where EQ-5D has not been administered. For conditions where EQ-5D was found to be inappropriate, including some vision disorders and for hearing, bolt-ons provide a promising solution. More primary research into the psychometric properties of the generic preference-based measures is required, particularly in cancer and for the assessment of reliability. Further research is needed for the development and valuation of bolt-ons to EQ-5D. FUNDING: This project was funded by the UK Medical Research Council (MRC) as part of the MRC-NIHR methodology research programme (reference G0901486) and will be published in full in Health Technology Assessment; Vol. 18, No. 9. See the NIHR Journals Library website for further project information.

Association between body mass index and health-related quality of life, and the impact of self-reported long-term conditions - cross-sectional study from the south Yorkshire cohort dataset.

BACKGROUND: We sought to quantify the relationship between body mass index (BMI) and health-related quality (HRQoL) of life, as measured by the EQ-5D, whilst controlling for potential confounders. In addition, we hypothesised that certain long-term conditions (LTCs), for which being overweight or obese is a known risk factor, may mediate the association between BMI and HRQoL. Hence the aim of our study was to explore the association between BMI and HRQoL, first controlling for confounders and then exploring the potential impact of LTCs. METHODS: We used baseline data from the South Yorkshire Cohort, a cross-sectional observational study which uses a cohort multiple randomised controlled trial design. For each EQ-5D health dimension we used logistic regression to model the probability of responding as having a problem for each of the five health dimensions. All continuous variables were modelled using fractional polynomials. We examined the impact on the coefficients for BMI of removing LTCs from our model. We considered the self-reported LTCs: diabetes, heart disease, stroke, cancer, osteoarthritis, breathing problems and high blood pressure. RESULTS: The dataset used in our analysis had data for 19,460 individuals, who had a mean EQ-5D score of 0.81 and a mean BMI of 26.3 kg/m². For each dimension, BMI and all of the LTCs were significant predictors. For overweight or obese individuals (BMI ≥ 25 kg/m²), each unit increase in BMI was associated with approximately a 3% increase in the odds of reporting a problem for the anxiety/depression dimension, a 8% increase for the mobility dimension, and approximately 6% for the remaining dimension s. Diabetes, heart disease, osteoarthritis and high blood pressure were identified as being potentially mediating variables for all of the dimensions. CONCLUSIONS: Compared to those of a normal weight (18.5 < BMI < 25 kg/m²), overweight and obese individuals had a reduced HRQoL, with each unit increase in BMI associated with approximately a 6% increase in the odds of reporting a problem on any of the EQ-5D health dimensions. There was evidence to suggest that diabetes, heart disease, osteoarthritis and high blood pressure may mediate the association between being overweight and HRQoL.

Genome-wide association study identifies loci at ATF7IP and KLK2 associated with percentage of circulating free PSA.

BACKGROUND: Percentage of free-to-total prostate-specific antigen (%fPSA) is an independent predictor of risk for prostate cancer among men with modestly elevated level of total PSA (tPSA) in blood. Physiological and pathological factors have been shown to influence the %fPSA value and diagnostic accuracy. MATERIALS/METHODS: To evaluate genetic determinants of %fPSA, we conducted a genome-wide association study of serum %fPSA by genotyping 642,584 single nucleotide polymorphisms (SNPs) in 3192 men of European ancestry, each with a tPSA level of 2.5 to 10 ng/ml, that were recruited in the REduction by DUtasteride of Prostate Cancer Events study. Single nucleotide polymorphisms (SNPs) with P < 10(-5) were further evaluated among the controls of a population-based case-control study in Sweden (2899 prostate cancer cases and 1722 male controls), including 464 controls having tPSA levels of 2.5 to 10 ng/ml. RESULTS: We identified two loci that were associated with %fPSA at a genome-wide significance level (P <5 x 10(-8)). The first associated SNP was rs3213764 (P = 6.45 x 10(-10)), a nonsynonymous variant (K530R) in the ATF7IP gene at 12p13. This variant was also nominally associated with tPSA (P = .015). The second locus was rs1354774 (P = 1.25 x 10(-12)), near KLK2 at 19q13, which was not associated with tPSA levels, and is separate from the rs17632542 locus at KLK3 that was previously associated with tPSA levels and prostate cancer risk. Neither rs3213764 nor rs1354774 was associated with prostate cancer risk or aggressiveness. CONCLUSIONS: These findings demonstrate that genetic variants at ATF7IP and KLK2 contribute to the variance of %fPSA.

Comparison of generic, condition-specific, and mapped health state utility values for multiple myeloma cancer.

OBJECTIVE: Resource allocation informed by cost-utility analysis requires that the benefits be comparable across patient groups and interventions. One option is to recommend the use of one generic utility measure, but this raises the issue of comparability when the preferred measure is inappropriate or unavailable. Many cancer trials do not include generic measures such as the EuroQol five-dimensional (EQ-5D) questionnaire and instead include condition-specific measures and use these to generate utility estimates. We analyze the comparability of generic, condition-specific, and mapped utility values for a multiple myeloma cancer patient data set. METHODS: Generic EQ-5D, condition-specific EORTC-8D, and EQ-5D utility values mapped from the EORTC QLQ-C30 were compared by using psychometric and statistical analysis to determine discrimination across severity groups, responsiveness, and agreement. RESULTS: Generic, condition-specific, and mapped utility estimates were responsive over time and show discriminative validity. The EQ-5D had higher responsiveness and detected a greater change across severity groups and treatment periods than did the EORTC-8D but has a higher proportion of responses at full health (12.8%). Differences in the EQ-5D and the EORTC-8D were due at least in part to differences in the classification system. Mapped EQ-5D estimates had a smaller SD and do not reflect the severe range of health states reported by using the EQ-5D. CONCLUSIONS: Our findings suggest that condition-specific EORTC-8D or mapped EQ-5D utility estimates are broadly comparable to directly obtained EQ-5D utilities for a multiple myeloma patient data set. However, EORTC-8D estimates captured changes in quality of life for patients in mild health states that were not captured by the EQ-5D, but estimated lower utility gains than did the use of the EQ-5D directly.

Identification of new differentially methylated genes that have potential functional consequences in prostate cancer.

Many differentially methylated genes have been identified in prostate cancer (PCa), primarily using candidate gene-based assays. Recently, several global DNA methylation profiles have been reported in PCa, however, each of these has weaknesses in terms of ability to observe global DNA methylation alterations in PCa. We hypothesize that there remains unidentified aberrant DNA methylation in PCa, which may be identified using higher resolution assay methods. We used the newly developed Illumina HumanMethylation450 BeadChip in PCa (n = 19) and adjacent normal tissues (n = 4) and combined these with gene expression data for identifying new DNA methylation that may have functional consequences in PCa development and progression. We also confirmed our methylation results in an independent data set. Two aberrant DNA methylation genes were validated among an additional 56 PCa samples and 55 adjacent normal tissues. A total 28,735 CpG sites showed significant differences in DNA methylation (FDR adjusted P<0.05), defined as a mean methylation difference of at least 20% between PCa and normal samples. Furthermore, a total of 122 genes had more than one differentially methylated CpG site in their promoter region and a gene expression pattern that was inverse to the direction of change in DNA methylation (e.g. decreased expression with increased methylation, and vice-versa). Aberrant DNA methylation of two genes, AOX1 and SPON2, were confirmed via bisulfate sequencing, with most of the respective CpG sites showing significant differences between tumor samples and normal tissues. The AOX1 promoter region showed hypermethylation in 92.6% of 54 tested PCa samples in contrast to only three out of 53 tested normal tissues. This study used a new BeadChip combined with gene expression data in PCa to identify novel differentially methylated CpG sites located within genes. The newly identified differentially methylated genes may be used as biomarkers for PCa diagnosis.

It's all in the name, or is it? The impact of labeling on health state values.

BACKGROUND: Many descriptions of health used in vignettes and condition-specific measures name the medical condition. This article assesses the impact of referring to the medical condition in the descriptions of health states valued by members of the general population. METHODS: A valuation study was conducted using face-to-face interviews involving the time trade-off valuation technique. All respondents valued essentially the same health states, but for each respondent, the descriptions featured an irritable bowel syndrome (IBS) label, a cancer label, or no label. Random effects generalized least squares regressions were used to estimate the impact of each label and experience of the condition on health state values. DATA: A sample of 241 members of the UK general population each valued 8 states, generating 1910 observations (response rate = 39%, completion rate = 99% for all states). RESULTS: The authors find no significant difference between health state values when the description contains no label or an IBS label. They find that the inclusion of a cancer label in health state descriptions affects health state values and that the impact is dependent on the severity of the state, with a significant reduction in values for more severe health states (up to -0.25 for the worst possible state) but no significant difference for mild states. CONCLUSIONS: A condition label can affect health state values, but this is dependent on the specific condition and severity. The authors recommend avoiding condition labels in health state descriptions (where possible) to ensure that values are not affected by prior knowledge or preconception of the condition that may distort the health state being valued.

Deriving a preference-based measure for cancer using the EORTC QLQ-C30.

OBJECTIVE: The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) is one of the most commonly used measures in cancer care but in its current form cannot be used in economic evaluation because it does not incorporate preferences. We address this gap by estimating a preference-based measure for cancer from the EORTC QLQ-C30. METHODS: Factor analysis, Rasch analysis, and other psychometric analyses were undertaken on a clinical trial dataset of 655 patients with multiple myeloma to derive a health state classification system amenable to valuation. Second a valuation study was conducted of 350 members of the UK general population using time trade-off. Mean and individual-level multivariate regression models were fitted to derive preference weights for the classification system. RESULTS: The health state classification system has eight dimensions (physical functioning, role functioning, social functioning, emotional functioning, pain, fatigue and sleep disturbance, nausea, constipation, and diarrhea) with four or five levels each. Regression models have few inconsistencies (0 to 2) in estimated preference weights and small mean absolute error ranges (0.046 to 0.054). CONCLUSIONS: It is feasible to derive a preference-based measure from the EORTC QLQ-C30 for use in economic evaluation. Future research will extend this to other countries and replicate across other patient groups.

Predicting gestational trophoblastic neoplasia (GTN): is urine hCG the answer?

BACKGROUND: Previous studies on the significance of hCG to predict gestational trophoblastic neoplasia (GTN) have been too small for robust conclusions to be reached. Our aim in this study was to analyse the significance of urine hCG in predicting GTN in a large population. METHODS: Details of 3926 patients were available for analysis. Information regarding age, dates of diagnosis and registration, urine hCG levels, antecedent pregnancy and chemotherapy were prospectively collected and used for analyses. Patients were stratified into different groups according to urine hCG level (IU/L); < 50, 50-99, 100-249, 250-499, 500-999, 1000-9999 and ≥10,000. Multivariate analyses were used to identify the prognostic indicators of GTN. RESULTS: Urine hCG and antecedent pregnancy were the most powerful indicators for developing GTN (P<0.01). None of the patients with partial mole and urine hCG <50 IU/L (Normal level=40 IU/L) developed GTN. The risk of GTN was >35% in all patients with urine hCG ≥500 IU/L. GTN developed in 70% of patients with complete mole and urine hCG ≥10,000 IU/L. CONCLUSION: Urine hCG is sensitive test for GTN. Urine hCG level is a powerful prognostic indicator for the GTN. Patients with partial mole could be safely discharged from the surveillance programme once their hCG have normalised. Patients with urine hCG ≥249 IU/L, whether partial or complete molar pregnancy, appear to benefit from intensive surveillance. Prophylactic chemotherapy could be considered when there are problems with surveillance.

Folate status and aberrant DNA methylation are associated with HPV infection and cervical pathogenesis.

Aberrant DNA methylation is a recognized feature of human cancers, and folate is directly involved in DNA methylation via one-carbon metabolism. Previous reports also suggest that folate status is associated with the natural history of human papillomavirus (HPV) infection. A cross-sectional study was conducted to test the hypothesis that folate status and aberrant DNA methylation show a progressive change across stages of cervical pathology from normal cells to cervical cancer. Additionally, we postulated that a gene-specific hypermethylation profile might be used as a predictive biomarker of cervical cancer risk. DNA hypermethylation of seven tumor suppressor genes, global DNA hypomethylation, systemic folate status, and HPV status were measured in 308 women with a diagnosis of normal cervix (n = 58), low-grade cervical intraepithelial neoplasia (CIN1; n = 68), high-grade cervical intraepithelial neoplasia (CIN2, n = 56; and CIN3, n = 76), or invasive cervical cancer (ICC; n = 50). Lower folate status was associated with high-risk HPV infection (P = 0.031) and with a diagnosis of cervical intraepithelial neoplasia or invasive cervical cancer (P < 0.05). Global DNA hypomethylation was greater in women with invasive cervical cancer than all other groups (P < 0.05). A cluster of three tumor suppressor genes, CDH1, DAPK, and HIC1, displayed a significantly increased frequency of promoter methylation with progressively more severe cervical neoplasia (P < 0.05). These findings are compatible with a role for folate in modulating the risk of cervical cancer, possibly through an influence over high-risk HPV infection. DAPK, CDH1, and HIC1 genes are potential biomarkers of cervical cancer risk.

Alpha-conotoxin Arenatus IB[V11L,V16D] [corrected] is a potent and selective antagonist at rat and human native alpha7 nicotinic acetylcholine receptors.

A recently developed alpha-conotoxin, alpha-conotoxin Arenatus IB-[V11L,V16D] (alpha-CtxArIB[V11L,V16D]) [corrected], is a potent and selective competitive antagonist at rat recombinant alpha7 nicotinic acetylcholine receptors (nAChRs), making it an attractive probe for this receptor subtype. alpha7 nAChRs are potential therapeutic targets that are widely expressed in both neuronal and non-neuronal tissues, where they are implicated in a variety of functions. In this study, we evaluate this toxin at rat and human native nAChRs. Functional alpha7 nAChR responses were evoked by choline plus the allosteric potentiator PNU-120596 [1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea] in rat PC12 cells and human SH-SY5Y cells loaded with calcium indicators. alpha-CtxArIB[V11L,V16D] specifically inhibited alpha7 nAChR-mediated increases in Ca2+ in PC12 cells. Responses to other stimuli, 5-I-A-85380 [5-iodo-3-(2(S)-azetidinylmethoxy)pyridine dihydrochloride], nicotine, or KCl, that did not activate alpha7 nAChRs were unaffected. Human alpha7 nAChRs were also sensitive to alpha-CtxArIB[V11L, V16D]; acetylcholine-evoked currents in Xenopus laevis oocytes expressing human alpha7 nAChRs were inhibited by alpha-CtxArIB[V11L,V16D] (IC(50), 3.4 nM) in a slowly reversible manner, with full recovery taking 15 min. This is consistent with the time course of recovery from blockade of rat alpha7 nAChRs in PC12 cells. alpha-CtxArIB[V11L,V16D] inhibited human native alpha7 nAChRs in SHSY5Y cells, activated by either choline or AR-R17779 [(2)-spiro[1-azabicyclo[2.2.2]octane-3,59-oxazolidin]-29-one] plus PNU-120596. Rat brain alpha7 nAChRs contribute to dopamine release from striatal minces; alpha-CtxArIB[V11L,V16D] (300 nM) selectively inhibited choline-evoked dopamine release without affecting responses evoked by nicotine that activates heteromeric nAChRs. This study establishes that alpha-CtxArIB[V11L,V16D] selectively inhibits human and rat native alpha7 nAChRs with comparable potency, making this a potentially useful antagonist for investigating alpha7 nAChR functions.

Peripheral nerve injury alters spinal nicotinic acetylcholine receptor pharmacology.

Nicotinic acetylcholine receptors are widely expressed in the rat spinal cord and modulate innocuous and nociceptive transmission. The present studies were designed to investigate the plasticity of spinal nicotinic acetylcholine receptors modulating mechanosensitive information following spinal nerve ligation. A tonic inhibitory cholinergic tone mediated by dihydro-beta-erythroidine- (DHbetaE) and methyllycaconitine- (MLA) sensitive nicotinic acetylcholine receptors was identified in the normal rat spinal cord and cholinergic tone at both populations of nicotinic acetylcholine receptors was lost ipsilateral to spinal nerve ligation. The administration of intrathecal nicotinic acetylcholine receptor agonists reduced mechanical paw pressure thresholds with a potency of epibatidine=A-85380>>nicotine>choline in the normal rat. Following spinal nerve ligation, intrathecal epibatidine and nicotine produced an ipsilateral antinociception, but intrathecal A-85380 and choline did not. The antinociceptive response to intrathecal nicotine was blocked with the alpha7 and alpha9alpha10-selective nicotinic acetylcholine receptor antagonist, MLA, and the alphabeta heteromeric nicotinic acetylcholine receptor antagonist, DHbetaE. The antinociceptive effects of both intrathecal nicotine and epibatidine were mediated by GABA(A) receptors. Spinal [(3)H]epibatidine saturation binding was unchanged in spinal nerve-ligated rats, but spinal nerve ligation did increase the ability of nicotine to displace [(3)H]epibatidine from spinal cord membranes. Spinal nerve ligation altered the expression of nicotinic acetylcholine receptor subunits ipsilaterally, with a large increase in the modulatory alpha5 subunit. Taken together these results suggest that pro- and antinociceptive populations of spinal nicotinic acetylcholine receptors modulate the transmission of mechanosensitive information and that spinal nerve ligation-induced changes in spinal nicotinic acetylcholine receptors likely result from a change in subunit composition rather than overt loss of nicotinic acetylcholine receptor subtypes.

Increased spinal dynorphin contributes to chronic nicotine-induced mechanical hypersensitivity in the rat.

Chronic nicotine administration has been shown previously to produce mechanical hypersensitivity in the rat although the mechanism of this effect is unknown. Rats treated with chronic systemic nicotine 3.6 or 8.6 mg/(kg day) for 14-21 days displayed mechanical hypersensitivity coincident with an increase of prodynorphin immunoreactivity and dynorphin content within the spinal cord. The administration of dynorphin antiserum intrathecally significantly attenuated chronic nicotine-induced mechanical hypersensitivity. Our results suggest that chronic nicotine administration produces an increase in spinal dynorphin content and release that contributes to mechanical hypersensitivity.