Measurement of changes in uterine and fibroid volume during treatment of heavy menstrual bleeding (HMB).

STUDY QUESTION: Does application of an unbiased method for analysis of magnetic resonance (MR) images reveal any effect on uterine or fibroid volume from treatment of heavy menstrual bleeding (HMB) with three 12-week courses of the selective progesterone receptor modulator ulipristal acetate (SPRM-UPA)? SUMMARY ANSWER: Application of an unbiased method for analysis of MR images showed that treatment of HMB with SPRM-UPA was not associated with a significant reduction in the volume of the uterus or in the volume of uterine fibroids. WHAT IS KNOWN ALREADY: SPRM-UPA shows therapeutic efficacy for treating HMB. However, the mechanism of action (MoA) is not well understood and there have been mixed reports, using potentially biased methodology, regarding whether SPRM-UPA has an effect on the volume of the uterus and fibroids. STUDY DESIGN SIZE DURATION: In a prospective clinical study (with no comparator), 19 women with HMB were treated over a period of 12 months with SPRM-UPA and uterine and fibroid size were assessed with high resolution structural MRI and stereology. PARTICIPANTS/MATERIALS SETTING METHODS: A cohort of 19 women aged 38-52 years (8 with and 11 without fibroids) were treated with three 12-week courses of 5 mg SPRM-UPA given daily, with four weeks off medication in-between treatment courses. Unbiased estimates of the volume of uterus and total volume of fibroids were obtained at baseline, and after 6 and 12 months of treatment, by using the Cavalieri method of modern design-based stereology in combination with magnetic resonance imaging (MRI). MAIN RESULTS AND THE ROLE OF CHANCE: Bland-Altman plots showed good intra-rater repeatability and good inter-rater reproducibility for measurement of the volume of both fibroids and the uterus. For the total patient cohort, two-way ANOVA did not show a significant reduction in the volume of the uterus after two or three treatment courses of SPRM-UPA (P = 0.51), which was also the case when the groups of women with and without fibroids were considered separately (P = 0.63). One-way ANOVA did not show a significant reduction in total fibroid volume in the eight patients with fibroids (P = 0.17). LIMITATIONS REASONS FOR CAUTION: The study has been performed in a relatively small cohort of women and simulations that have subsequently been performed using the acquired data have shown that for three time points and a group size of up to 50, with alpha (Type I Error) and beta (Type II Error) set to 95% significance and 80% power, respectively, at least 35 patients would need to be recruited in order for the null hypothesis (that there is no significant reduction in total fibroid volume) to be potentially rejected. WIDER IMPLICATIONS OF THE FINDINGS: The imaging protocol that we have developed represents a generic paradigm for measuring the volume of the uterus and uterine fibroids that can be readily incorporated in future studies of medical treatments of HMB. In the present study, SPRM-UPA failed to produce a significant reduction in the volume of the uterus or the total volume of fibroids (which were present in approximately half of the patients) after either two or three 12-week courses of treatment. This finding represents a new insight in respect of the management of HMB using treatment strategies that target hormone-dependence. STUDY FUNDING/COMPETING INTERESTS: The UPA Versus Conventional Management of HMB (UCON) trial was funded by the EME Programme (Medical Research Council (MRC) and National Institutes of Health Research (NIHR)) (12/206/52). The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care.Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. H.C. has clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (All paid to Institution) for Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc., and Myovant Sciences GmbH. H.C. has received royalties from UpToDate for an article on abnormal uterine bleeding. L.W. has received grant funding from Roche Diagnostics (Paid to Institution). All other authors have no conflicts to declare. TRIAL REGISTRATION NUMBER: The study reported here is an embedded mechanism of action study (no comparator) within the UCON clinical trial (registration ISRCTN: 20426843).

EPAC-lung: pooled analysis of circulating tumour cells in advanced non-small cell lung cancer.

INTRODUCTION: We assessed the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with advanced non-small cell lung cancer (NSCLC) by undertaking a pooled analysis of individual patient data. METHODS: Nine European NSCLC CTC centres were asked to provide reported/unreported pseudo-anonymised data for patients with advanced NSCLC who participated in CellSearch CTC studies from January 2003 to March 2017. We used Cox regression models, stratified by centres, to establish the association between CTC count and survival. We assessed the added value of CTCs to prognostic clinicopathological models using likelihood ratio (LR) statistics and c-indices. RESULTS: Seven out of nine eligible centres provided data for 550 patients with prognostic information for overall survival. CTC counts of ≥2 and ≥ 5 per 7·5 mL were associated with reduced progression-free survival (≥2 CTCs: hazard ratio [HR] = 1.72, p < 0·001; ≥5 CTCs: HR = 2.21, p < 0·001) and overall survival (≥2 CTCs: HR = 2·18, p < 0·001; ≥5 CTCs: HR = 2·75, p < 0·001), respectively. Survival prediction was significantly improved by addition of baseline CTC count to LR clinicopathological models (log-transformed CTCs p < 0·001; ≥2 CTCs p < 0·001; ≥5 CTCs p ≤ 0·001 for both survival end-points), whereas moderate improvements were observed with the use of c-index models. There was some evidence of between-centre heterogeneity, especially when examining continuous counts of CTCs. CONCLUSIONS: These data confirm CTCs as an independent prognostic indicator of progression-free survival and overall survival in advanced NSCLC and also reveal some evidence of between-centre heterogeneity. CTC count improves prognostication when added to full clinicopathological predictive models.

Prognostic value of circulating tumour cells in limited-stage small-cell lung cancer: analysis of the concurrent once-daily versus twice-daily radiotherapy (CONVERT) randomised controlled trial.

BACKGROUND: The clinical significance of circulating tumour cells (CTCs) in limited-stage small-cell lung cancer (LS-SCLC) is not well defined. We report a planned exploratory analysis of the prevalence and prognostic value of CTCs in LS-SCLC patients enrolled within the phase III randomised CONVERT (concurrent once-daily versus twice-daily chemoradiotherapy) trial. PATIENTS AND METHODS: Baseline blood samples were enumerated for CTCs using CellSearch in 75 patients with LS-SCLC who were enrolled in the CONVERT trial and randomised between twice- and once-daily concurrent chemoradiation. Standard statistical methods were used for correlations of CTCs with clinical factors. Log-rank test and Cox regression analyses were applied to establish the associations of 2, 15 and 50 CTC thresholds with progression-free survival (PFS) and overall survival (OS). An optimal CTC count threshold for LS-SCLC was established. RESULTS: CTCs were detected in 60% (45/75) of patients (range 0-3750). CTC count thresholds of 2, 15 and 50 CTCs all significantly correlate with PFS and OS. An optimal CTC count threshold in LS-SCLC was established at 15 CTCs, defining 'favourable' and 'unfavourable' prognostic risk groups. The median OS in <15 versus ≥15 CTCs was 26.7 versus 5.9 m (P = 0.001). The presence of ≥15 CTCs at baseline independently predicted ≤1 year survival in 70% and ≤2 years survival in 100% of patients. CONCLUSION: We report the prognostic value of baseline CTC count in an exclusive LS-SCLC population at thresholds of 2, 15 and 50 CTCs. Specific to LS-SCLC, ≥15 CTCs was associated with worse PFS and OS independent of all other factors and predicted ≤2 years survival. These results may improve disease stratification in future clinical trial designs and aid clinical decision making. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00433563.

Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project.

Background: Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Methods: Clinically annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test. Results: Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases. Conclusion: Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

Diabetes UK Position Statement. Competency frameworks in diabetes.

The quality, skills and attitudes of staff working in the healthcare system are central to multidisciplinary learning and working, and to the delivery of the quality of care patients expect. Patients want to know that the staff supporting them have the right knowledge and attitudes to work in partnership, particularly for conditions such as diabetes where 95% of all care is delivered by the person with diabetes themselves. With the current changes in the NHS structures in England, and the potential for greater variation in the types of 'qualified provider', along with the recent scandal at Mid-Staffordshire Hospital, staff need to be shown to be competent and named/accredited or recognized as such. This will help to restore faith in an increasingly devolved delivery structure. The education and validation of competency needs to be consistently delivered and assured to ensure standards are maintained for different roles and disciplines across each UK nation. Diabetes UK recommends that all NHS organizations prioritize healthcare professional education, training and competency through the implementation of a National Diabetes Competency Framework and the phased approach to delivery to address this need.

The current status of diabetes professional educational standards and competencies in the UK--a position statement from the Diabetes UK Healthcare Professional Education Competency Framework Task and Finish Group.

Diabetes is a significant health concern, both in the UK and globally. Management can be complex, often requiring high levels of knowledge and skills in order to provide high-quality and safe care. The provision of good, safe, quality care lies within the foundations of healthcare education, continuing professional development and evidence-based practice, which are inseparable and part of a continuum during the career of any health professional. Sound education provides the launch pad for effective clinical management and positive patient experiences. This position paper reviews and discusses work undertaken by a Working Group under the auspices of Diabetes UK with the remit of considering all health professional educational issues for people delivering care to people with diabetes. This work has scoped the availability of education for those within the healthcare system who may directly or indirectly encounter people with diabetes and reviews alignment to existing competency frameworks within the UK's National Health Service.

Noggin arrests stromal cell differentiation in vitro.

Noggin is a glycoprotein that binds bone morphogenetic proteins (BMPs) selectively and, when added to osteoblasts, it opposes the effects of BMPs. However, the consequences of its continued expression in stromal cells are not known. We investigated the effects of noggin overexpression under the control of a constitutive promoter, on murine ST-2 stromal cells, and its impact on stromal cells from transgenic mice overexpressing noggin under the control of the osteocalcin promoter. ST-2 cells were transduced with a retroviral vector (pLPCX) or a vector driving noggin (pLPCX noggin). Untreated (pLPCX) ST-2 cells developed the appearance of mineralized nodules and expressed osteocalcin. pLPCX noggin delayed the appearance of mineralized nodules and prevented the expression of osteocalcin. Noggin also prevented the cortisol-dependent induction of peroxisome proliferator-activated receptor gamma2 and adipsin transcripts, indicating a generalized inhibition of cell differentiation. Primary stromal cells from noggin transgenic mice displayed impaired differentiation when compared to cells from wild-type animals and did not express osteocalcin mRNA. In conclusion, noggin arrests the differentiation of stromal cells, preventing cellular maturation.

Technician, friend, detective, and healer: family physicians' responses to emotional distress.

OBJECTIVE: We sought to develop a typology of physicians' responses to patients' expressed mental health needs to better understand the gap between idealized practice and actual care for emotional distress and mental health problems. STUDY DESIGN: We used a multimethod comparative case study design of 18 family practices that included detailed descriptive field notes from direct observation of 1637 outpatient visits. An immersion/crystallization approach was used to explore physicians' responses to emotional distress and apparent mental health issues. POPULATION: A total of 379 outpatient encounters were reviewed from a purposeful sample of 13 family physicians from the 57 clinicians observed. OUTCOMES MEASURED: Descriptive field notes of outpatient visits were examined for emotional content and physicians' responses to emotional distress. RESULTS: Analyses revealed a 3-phase process by which physicians responded to emotional distress: recognition, triage, and management. The analyses also uncovered a 4-quadrant typology of management based on the physician's philosophy (biomedical vs holistic) and skill level (basic vs more advanced). CONCLUSIONS: Physicians appear to manage mental health issues by using 1 of 4 approaches based on their philosophy and core set of skills. Physician education and practice improvement should be tailored to build on physicians' natural philosophical proclivity and psychosocial skills.

Carcinogenic effects of intracolonic benzo[a]pyrene in beta-naphthoflavone-induced mice.

Benzo[a]pyrene (BP) was administered intracolonically to ICR/Ha and C57Bl/6 female mice, 1 mg/mouse, once weekly for 14 weeks. Half of the mice received beta-naphthoflavone (beta-NF, a mixed-function oxygenase inducer) i.p. 24 h prior to the BP. No colonic neoplasms were found in any of the mice after 18 months. However, the BP treatment did cause a significant increase in numbers of primary lung tumors, forestomach papillomas, mammary carcinomas, and sarcomas in one or both strains, relative to controls, and the incidence of all of these except for the sarcomas was significantly reduced by treatment with beta-NF prior to BP. Overall, the beta-NF pretreatment reduced total incidence of neoplasms by about 30% in the ICR/Ha mice and by about 60% in the C57Bl/6 mice, and did not potentiate the action of the carcinogen in any organ.

Reduction in the transplacental carcinogenic effect of methylcholanthrene in mice by prior treatment with beta-naphthoflavone.

Conversion of 14C-benzo[alpha]pyrene (BP) to alkali-soluble and water-phase products, as a measure of aryl hydrocarbon metabolism, was assayed on day 18 of gestation in the livers of pregnant C57BL/6 females and their (C57BL/6 x BALB/c)F1 fetuses. BP metabolism was inducible in both maternal and fetal livers by beta-naphthoflavone (beta-NF), injected ip on day 16 of gestation at doses of 25-130 mg/kg. At 25 and 75 mg/kg beta-NF, fetal liver metabolism of BP was induced 1.5- and 4.5-fold, respectively. The corresponding results for maternal liver indicated no effect at 25 mg/kg and 2.6-fold induction at 75 mg/kg. In a complementary carcinogenesis assay, pregnant mothers were injected ip with beta-NF (25 or 75 mg/kg) on day 15 of gestation and 3-methylcholanthrene (MC) (30 or 150 mg/kg) on day 17. Appropriate vehicle-injected control mice were also obtained. The progeny were examined for lung tumors at 28 weeks of age. The average number of lung tumors per mouse caused by 150 mg/kg MC was significantly reduced by prior treatment with beta-NF, to an extent depending on the dose of the inducer. With the 75 mg/kg dose of beta-NF, the incidence of lung tumors was reduced by half. Induction of carcinogen detoxification in maternal, fetal, and/or placental tissue is a possible mechanism by which beta-NF protected against transplacental MC tumorigenesis.

Lung tumorigenesis in mice after chronic exposure in early life to a low dose of dimethylnitrosamine.

Strain A female mice were exposed to 10 ppb dimethylnitrosamine (DMN) in their drinking water for 4 weeks before mating. Treatment was continued through pregnancy and lactation and after weaning until the progeny were 22 weeks old. The incidence of primary lung tumors among the treated progeny (23%) was significantly higher (P less than 0.021) than that among controls (8%). The effect of the DMN was greatest among the males: 32% had lung tumors, compared with 4% of the control males (P less than 0.016). The DMN-exposed females also had a higher lung tumor incidence than did the controls, but the difference was not of statistical significance. These results demonstrate carcinogenicity of DMN at a dose approaching amounts possibly encountered by the human population as a result of environmental exposure.