Impact of Oncotype DX breast Recurrence Score testing on adjuvant chemotherapy use in early breast cancer: Real world experience in Greater Manchester, UK.

BACKGROUND: The National Institute for Health and Clinical Excellence (NICE) recommended the Oncotype DX® Breast Recurrence Score® (RS) assay as an option for informing adjuvant chemotherapy decisions in node-negative, oestrogen receptor (ER)+, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer assessed to be at intermediate risk of recurrence based on clinicopathological factors. We evaluated the impact of RS testing on adjuvant chemotherapy decision-making in routine clinical practice in a UK Cancer Network. METHODS: RS testing was performed in 201 females with newly diagnosed, ER+, HER2-negative, invasive breast cancer who underwent breast surgery with curative intent, were calculated to have a >3% overall survival benefit at 10 years from adjuvant chemotherapy based on PREDICT, and were considered for adjuvant chemotherapy. The impact of RS testing on adjuvant treatment decisions/associated cost was assessed. RESULTS: In all patients, the multi-disciplinary team recommended chemotherapy but the RS result allowed 127/201 patients (63.2%) to avoid unnecessary adjuvant chemotherapy. Amongst ER+, HER2-negative, node-negative patients (eligible for Oncotype DX testing in UK guidelines), 60.3% were spared chemotherapy. In node-positive patients, the assay reduced the use of chemotherapy by 69.2%. The use of RS testing to guide treatment in these 201 patients was associated with significant cost saving (when considering the cost of RS testing for all patients plus chemotherapy and its associated cost for 74 patients). CONCLUSIONS: Incorporating RS testing into routine clinical practice for selected node-negative and node-positive breast cancer patients significantly reduces the use of chemotherapy (p < 0.001) with its associated morbidity and costs.

National Institute of Academic Anaesthesia research priority setting exercise.

BACKGROUND: Formal research priority setting is a recognized way of identifying important clinical research questions and promoting these as topics for commissioned research. This paper describes a research priority setting exercise conducted by the National Institute of Academic Anaesthesia (NIAA). METHODS: Possible research questions were identified from a questionnaire sent to holders of the Final Fellowship in Anaesthesia in Great Britain and Ireland and to lay representatives. The responses to the first questionnaire were collated to produce a list of potential research questions which were then sent to the same constituency for scoring. The results of this scoring process were considered by an expert panel and statements of research need generated for selected questions. The questions from the first round were also reviewed with the help of representatives of NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC). RESULTS: For the first questionnaire, 308 responses with 447 suggestions for research were received. A total of 15 questions were included in the second questionnaire, for which 2226 responses were received. The expert panel identified five questions for prioritization. A further nine were identified from discussions with representatives of NETSCC. CONCLUSIONS: A total of 14 research priorities were identified by the exercise, two of which have been submitted to the NIHR Health Technology Assessment (HTA) programme as statements of research need. Potential funding streams for the remaining questions are being sought. We discuss some implications of this exercise for research strategy in the speciality.

The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review.

BACKGROUND: Breast cancer is the most common cancer affecting women in the UK. Tamoxifen (TAM) is considered as the standard of care for many women with oestrogen receptor positive breast cancer. However, wide variability in the response of individuals to drugs at the same doses may occur, which may be a result of interindividual genetic differences (pharmacogenetics). TAM is known to be metabolised to its active metabolites N-desmethyl TAM and 4-hydroxytamoxifen by a number of CYP450 enzymes, including CYP2D6, CYP3A4, CYP2C9, CYP2C19 and CYP2B6. N-desmethyl TAM is further metabolised to endoxifen by CYP2D6. Endoxifen, which is also formed via the action of CYP2D6, is 30- to 100-fold more potent than TAM in suppressing oestrogen-dependent cell proliferation, and is considered an entity responsible for significant pharmacological effects of TAM. Thus, an association between the cytochrome P450 2D6 (CYP2D6) genotype and phenotype (expected drug effects) is believed to exist and it has been postulated that CYP2D6 testing may play a role in optimising an individual's adjuvant hormonal treatment. OBJECTIVES: To determine whether or not testing for cytochrome P450 2D6 (CYP2D6) polymorphisms in women with early hormone receptor positive breast cancer leads to improvement in outcomes, is useful for health decision-making and is a cost-effective use of health-care resources. DATA SOURCES: Relevant electronic databases and websites including MEDLINE, EMBASE and HuGENet [Centers for Disease Control and Prevention (Office of Public Health Genomics), Human Genome Epidemiology Network] were searched until July 2009. Further studies that became known to the authors via relevant conferences or e-mail alerts from an automatically updated search of the Scopus database were also included as the review progressed, up to March 2010. REVIEW METHODS: A systematic review of the clinical effectiveness and cost-effectiveness of CYP2D6 testing was undertaken. As it was not possible to conduct meta-analyses, data were extracted into structured tables and narratively discussed. An exploratory analysis of sensitivity and specificity was undertaken. A review of economic evaluations and models of CYP2D6 testing for patients treated with TAM was also carried out. RESULTS: A total of 25 cohorts were identified which examined clinical efficacy (overall survival and relapse/recurrence), adverse events and endoxifen plasma concentrations by genotype/phenotype. Significantly, six cohorts suggest extensive metabolisers (Ems) appear to have better outcomes than either poor metabolisers (PMs) or PMs + intermediate metabolisers in terms of relapse/recurrence; however, three cohorts report apparently poorer outcomes for EMs (albeit not statistically significant). There was heterogeneity across the studies in terms of the patient population, alleles tested and outcomes used and defined. One decision model proposing a strategy for CYP2D6 testing for TAM was identified, but this was not suitable for developing a model to examine the cost-effectiveness of CYP2D6 testing. It was not possible to produce a de novo model because of a lack of data to populate it. CONCLUSION: This is a relatively new area of research that is evolving rapidly and, although international consortia are collaborating, the data are limited and conflicting. Therefore, it is not possible to recommend pharmacogenetic testing in this patient population. Future research needs to focus on which alleles (including, or in addition to, those related to CYP2D6) reflect patient response, the link between endoxifen levels and clinical outcomes, and the appropriate pathways for implementation of such pharmacogenetic testing in patient care pathways.

Perioperative management of patients undergoing non-cardiac vascular surgery.

Patients undergoing non-cardiac vascular surgery have arterial disease affecting more than one vascular bed and commonly have multiple significant co-morbidities. The surgical and anaesthetic teams are asked to address pre-, peri- and postoperative management issues relating not only to the surgery but arising from these co-morbidities. Here we review the strategies and rationale for the optimisation of these high risk patients.

Brain donation for research: who donates and why?

Understanding what influences people to donate or not donate body organs is critical for the future of transplant surgery and medical research. Are people involved with a brain donor program for research influenced by the same factors, and are they also donors for organ transplantation? Using web-based technology, people involved in an Australian brain donation program (for research) were asked to complete a questionnaire designed to elicit demographic information, motivational factors and information about involvement in organ transplantation programs. The response rate was 82%. The majority of people involved in the program are young, well-educated Australian females. Seventy-eight percent are involved in other organ and tissue donation programs. People involved in the 'Using our Brains' program are the same group as those who are organ and tissue donors. An improvement in the overall donation rate might be possible if the resources of the research and transplant organisations were combined.

Low socioeconomic class is a risk factor for upper and lower gastrointestinal symptoms: a population based study in 15 000 Australian adults.

BACKGROUND: The association of social class with health has been extensively studied, yet relationships between social class and gastrointestinal symptoms remain almost unexplored. AIMS: To examine relationships between social class and gastrointestinal symptoms in a population sample. METHODS: The prevalence of 16 troublesome gastrointestinal symptoms was determined by a postal questionnaire sent to 15 000 subjects (response rate 60%) and compared with a validated composite measure of socioeconomic status (index of relative socioeconomic disadvantage). Comparisons across social class were explored for five symptom categories (oesophageal symptoms; upper dysmotility symptoms; bowel symptoms; diarrhoea; and constipation). Results are reported as age standardised rate ratios with the most advantaged social class as the reference category. RESULTS: There were clear trends for the prevalence rates of all gastrointestinal symptoms to increase with decreasing social class. These trends were particularly strong for the five symptom categories. Lower social class was associated with a significantly (p<0.0001) higher number of symptoms reported overall and with a higher proportion of individuals reporting 1-2 symptoms and more than five symptoms. In both sexes, the most pronounced effects for subjects in the lowest social class were found for constipation (males: rate ratio 1.83 (95% confidence intervals (CI) 1.16-2.51); females: rate ratio 1.68 (95% CI 1.31-2.04)) and upper dysmotility symptoms (males: rate ratio 1.45 (95% CI 1.02-1.88); females: rate ratio 1.35 (95% CI 1.07-1.63)). Oesophageal symptoms and diarrhoea were not associated with social class. CONCLUSIONS: Troublesome gastrointestinal symptoms are linked to socioeconomic status with more symptoms reported by subjects in low socioeconomic classes. Low socioeconomic class should be considered a risk factor for both upper and lower gastrointestinal symptoms.

The use of pre-conceptional folic acid as an indicator of uptake of a health message amongst white and Bangladeshi women in Tower Hamlets, east London.

BACKGROUND: The benefit of folic acid is a simple health promotion message of proven effectiveness that is particularly pertinent to a young population with a high birth rate. OBJECTIVE: The aim of the present study was to compare the uptake of a folic acid health message in two different ethnic groups. METHODS: Community antenatal teams in Tower Hamlets were asked to recruit women attending for a booking between October 1997 and July 1998 to the study. Tower Hamlets, in east London, is one of the poorest areas in England and Wales, with an ethnically diverse population. A questionnaire enquiring about age, employment, level of education, use of folic acid in their current pregnancy, understanding of the benefits of folic acid and self-described ethnic group was administered verbally immediately before the booking appointment to those women who agreed to participate. RESULTS: Completed questionnaires were received on 249 women. Univariate analysis showed that white women were 5.7 [95% confidence interval (CI) 2.5, 13.2] times more likely to have taken folic acid supplements before conception than Bangladeshi women. Having controlled for the variables, age, school leaving age, social class, parity, planned pregnancy and 'heard of folic acid', ethnic status remained a significant predictor of taking folic acid, with the odds ratio dropping to 5.2 with a 95% CI (1.1, 25.2). CONCLUSION: The Bangladeshi community in the UK have been shown to have poor access to health information sources, which is consistent with the results of this survey, which shows that a simple and important message has not been acted upon equally by white and Bangladeshi women in east London. This survey lends support to the view that resources and innovative forms of health promotion are needed to ensure that ethnic minority groups have adequate access to health promotion messages.

A community-based occupational enrichment program for captive chimpanzees.

The authors describe a cost-effective program for providing chimpanzee enrichment that at the same time educates the local community about the care of these animals in research.

Intranasal midazolam for premedication of children undergoing day-case anaesthesia: comparison of two delivery systems with assessment of intra-observer variability.

Midazolam is often used for paediatric premedication. We have compared two methods of administering midazolam intranasally in 44 surgical day-case children allocated randomly to receive midazolam 0.2 mg kg-1 as drops or midazolam 0.1 mg kg-1 from an intranasal spray device. Behaviour was recorded on a four-point scale by the parent, nurse and anaesthetist. Coefficients were obtained representing the change in behaviour score. There was no significant difference in method of administration (coefficient 0.13, P = 0.39). Children were significantly more distressed at the time of premedication and at the time of venous cannulation (coefficients 1.31 and 0.70) than at baseline. There was no significant difference in the assessments between observers. Midazolam by either method was equally effective but acceptability of the premedication was poor in both groups. Intranasal midazolam cannot be recommended as a method for routine premedication of young children.

Maintenance of therapeutic plasma aprotinin levels during prolonged cardiopulmonary bypass using a large-dose regimen.

Aprotinin concentrations in the range of 127-191 kallikrein inactivator units (KIU)/mL at the end of cardiopulmonary bypass (CPB) (< 2 h duration) reduce transfusion requirements. It has been suggested that prolonged CPB may require higher infusion rates which significantly increase cost. We tested the hypothesis that large-dose aprotinin maintains therapeutic plasma levels during prolonged periods of CPB (< 2 h). Aprotinin was administered as follows: 2 x 10(6) KIU upon skin incision; 0.5 x 10(6) KIU/h x 4-h infusion on initiation of CPB; and 2 x 10(6) KIU added to the CPB prime solution. Aprotinin activity was measured 1) 30 min after initiation of drug administration (Pre-CPB); 2) 30 min after initiation of CPB (CPB + 30); 3) 90 min after initiation of CPB (CPB + 90); and 4) at CPB termination (End CPB). CPB duration (mean +/- SD) was 158 +/- 51 min. Plasma aprotinin concentrations (KIU/mL, mean +/- SD) were: 234 +/- 30 at Pre-CPB; 229 +/- 35 at CPB + 30; 184 +/- 27 at CPB + 90; and 179 +/- 22 at End CPB. In all patients, aprotinin levels at the completion of CPB were in the range previously reported to be effective. The authors conclude that large-dose regimen limited to 6 x 10(6) KIU maintained therapeutic plasma aprotinin concentrations during prolonged CPB.

Severity-adjusted differences in hospital utilization by gender.

Gender-based differences in hospital use may result from biological differences or may suggest problems of access to health services and quality of care. We hypothesized that there should be no difference in hospital care between men and women, given the same diagnosis. Hospitalizations were characterized by severity of illness, as this may indicate the timeliness of hospital care. Hospitalizations may be too late (with higher severity of illness) resulting in long stays and high costs, or too early (with lower severity of illness) resulting in care that could be given in alternative treatment settings. Three abdominal conditions were examined which could be misdiagnosed or confused with other diseases involving the female reproductive system: appendicitis, diverticulitis, and cholecystitis. The National Hospital Discharge Survey (NHDS) was used for analysis. Disease staging was used to assign a severity of illness indicator, ranging from stage 1 (conditions with no complications) to stage 3 (multiple site involvement, poor prognosis). For each disease, the percentage of discharges and the age-adjusted discharge rate per 1000 population was examined by stage of illness and gender. For appendectomy, there was a significantly greater percentage of men at stage 1 (lower severity) compared to women (73% versus 67%). For diverticular disease, women had higher proportions of stage 2/3 discharges than men for both medical and surgical hospitalizations. For cholecystitis, women had a greater percentage of hospitalizations at stage 1 than men, notably for surgical treatment (63% compared with 38%), although more men were admitted at stage 2 for both medical and surgical treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Orthodontic treatment needs in Westmead Hospital Dental Clinical School.

One hundred and fifty-four adolescents, 76 female and 78 male consented to take part in this survey. The two authors examined and assessed them for dental aesthetics, malocclusion related features and TMJ related signs. The patients were also questioned about their opinion of dental aesthetics, their interest in having orthodontic treatment and their TMJ symptoms. Only 63 per cent of the adolescents who were considered suitable for orthodontic treatment expressed an interest in wanting treatment. Twenty-seven per cent of patients had signs and/or symptoms of TMJ disturbance. No association was found between individual malocclusion problems and TMJ signs and symptoms. The authors considered 56.5 per cent of the total group for orthodontic treatment, the majority for aesthetic reasons, and placed them into high, medium and low priority groups. Fixed appliance therapy for both arches was the recommended type of treatment for most patients.

Evaluating the competence of physicians in practice: from peer review to performance assessment.

Evaluation of physician competence has traditionally been defined by the medical profession largely through standardized tests and board certifying examinations. However, a level of physician evaluation that takes place outside academic medical centers and certifying boards is rapidly developing. This article describes three programs for such physician evaluation: (1) the program of US Healthcare, a national managed health care company; (2) the DEMPAQ--Developing and Evaluating Methods to Promote Ambulatory Care Quality--project, a joint research effort between Harvard University (Cambridge, Massachusetts) and the State of Maryland's (and District of Columbia's) Peer Review Organization (PRO); and (3) a project initiated by the American College of Physicians (ACP) in Philadelphia, Pennsylvania, to assess both medical competence and technical performance in the hospital setting. The authors argue for the need to inform physicians-in-training about the types of evaluation to which they will be subjected over the courses of their careers. In order to further this goal, the authors advocate increased collaboration between leaders in the academic setting and those spearheading these new programs for assessment of physician performance.

A re-assessment of the role of protein kinase C in glucose-stimulated insulin secretion.

Isolated rat islets of Langerhans which had been pretreated with 200 nM-phorbol 12-myristate 13-acetate (PMA) for 20-24 h, a treatment reported in other cell types to deplete cells of protein kinase C activity, were found not to contain detectable Ca2+/phospholipid-dependent protein kinase activity. These islets did not secrete insulin in response to a subsequent exposure to PMA (0.1 or 1 microM) during a 30 min incubation, although insulin secretion could be stimulated by 20 mM-glucose, a response which was enhanced by 20 microM-forskolin. PMA-pretreated islets that had been permeabilized by high-voltage discharge showed unimpaired secretory responses to an increase in Ca2+ concentration, cyclic AMP and forskolin. These results suggest that (i) pretreatment of islets with tumour-promoting phorbol esters may be a useful means of investigating the role of protein kinase C in stimulus-secretion coupling in the pancreatic beta-cell and (ii) protein kinase C may not play an essential role in glucose-induced insulin secretion.

Assessment of the antidiabetic activity of epicatechin in streptozotocin-diabetic and spontaneously diabetic BB/E rats.

(-)-Epicatechin has previously been suggested to rapidly reverse alloxan diabetes in rats. We have assessed the therapeutic value of the compound in two further animal models of insulin-dependent diabetes mellitus, namely streptozotocin-diabetic rats and the spontaneously diabetic BB/E rat. There was no indication of a reversal of established diabetes in either the streptozotocin-diabetic or the spontaneously diabetic BB/E rats. Moreover, epicatechin also failed to halt the progression of the disease in prediabetic BB/E rats. Earlier claims of the potential use of epicatechin as an antidiabetic agent must therefore be treated with some caution.

Assessment of palatal height in children.

In this study a palatal index (P.I.) was established for 121 randomly selected normal Australian children. Mean P.I. indices were compared in the primary, mixed and permanent dentitions. A subjective assessment of relative palatal height was also carried out by two independent examiners and an attempt was made to examine the reliability of the subjective assessment, and its validity compared with the P.I. Measurements were recorded on stone casts at Level 1 (distal to the primary second molars/second premolars) and Level 2 (between primary first and second molar/first and second premolars). At Level 1 the mean P.I. increased significantly from the primary to the mixed and permanent dentitions. At level 2 the P.I. remained stable. Findings indicate that subjective assessment of relative palatal height was fairly reliable: there was approximately 80% interexaminer and intraexaminer agreements. Subjective assessment of palatal height correlated reasonably well with the P.I.