Meta-analysis: folic acid in the chemoprevention of colorectal adenomas and colorectal cancer.

BACKGROUND: Folic acid has been identified as a possible agent for the chemoprevention of colorectal cancer. AIM: To assess the effectiveness of folic acid in reducing the recurrence of adenomas (precursors of colorectal cancer) among populations with a history of adenomas and the incidence of colorectal cancer within average-risk populations. METHODS: Systematic review of randomized controlled trials comparing folic acid alone, or with other agents, vs. placebo. Eight databases were searched for relevant trials. Meta-analysis was performed. RESULTS: The literature search retrieved 3785 citations. Six studies met the inclusion criteria. Meta-analysis of three studies in individuals with a history of adenomas showed no statistically significant difference in the relative risk of adenoma recurrence (RR 0.93, P = 0.27). A sensitivity analysis of the two higher quality trials changed the direction of effect (RR 1.16, P = 0.11). Meta-analysis of three trials in general populations demonstrated no statistically significant effect on the relative risk of colorectal cancer (RR 1.13, P = 0.54). In all three analyses, outcome event rates were higher in individuals receiving folic acid. CONCLUSION: There is no evidence that folic acid is effective in the chemoprevention of colorectal adenomas or colorectal cancer for any population.

Trastuzumab for the treatment of primary breast cancer in HER2-positive women: a single technology appraisal.

This paper presents a summary of the evidence review group (ERG) report into the the clinical and cost-effectiveness of trastuzumab for the treatment of primary breast cancer in human epidermal growth factor 2 (HER2)-positive women based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's scope restricts the intervention to intravenous trastuzumab given for 1 year after surgery and after the completion of standard adjuvant chemotherapy, and the comparator to standard therapy without trastuzumab. The clinical rationale for the duration of treatment in the scope is open to question and leads to the exclsuion of one potentially relevant trial. The submitted evidence reports that the 3-weekly regimen of trastuzumab produced a relative reduction in all-cause mortality of 24-33%. Meta-analysis of all available studies based on 12 months of trastuzumab showed that there was a statistically significant 30% relative improvement in overall survival using the 3-weekly regimen. A study looking at weekly cycles of trastuzumab, excluded in the manufacturer's submission, produced a relative reduction in all-cause mortality of 59%, which was not statistically significant. All included studies showed a statistically significant difference in the risk of recurrence or death from any cause (disease-free survival), favouring trastuzumab. There was a statistically significant increase in the relative risk of a serious adverse event in women treated with 3-weekly cycles of trastuzumab, with no excess toxicity in the study evaluating weekly cycles. Estimates of cost-effectiveness provided by the manufacturer were based on data from the HERA trial using the 3-weekly regimen of trastuzumab. The economic model was a state-transition model that compared the lifetime impact of adding 1 year of trastuzumab therapy to standard care with standard care alone. The initial cost-effectiveness estimate was 5687 pounds per additional quality-adjusted life-year (QALY) gained, rising to a maximum of 8689 pounds upon one-way sensitivity analysis. The base-case estimate of cost-effectiveness was subsequently revised by the manufacturer, resulting in an estimated incremental cost per additional QALY gained of 2387 pounds. A number of assumptions behind the manufacturer's model may be optimistic and could mean that the incremental costs per QALY gained were underestimated. Additional analysis carried out by the evidence review group concluded that the incremental cost-effectiveness ratio (ICER) is expected to be around 20,000 pounds to 30,000 pounds. The addition of potential long-term cardiac events could push the ICER above 30,000 pounds, although there is no long-term evidence to date surrounding this issue. In addition, the small study excluded from the manufacturer's submission raises the possibility of an equally effective but shorter regimen, incurring lower cost and toxicity and with greater patient convenience. The guidance issued by NICE in June 2006 as a result of the STA states that trastuzumab, given at 3-week intervals for 1 year or until disease recurrence, is recommended as a treatment option for women with early-stage HER2-positive breast cancer following surgery, chemotherapy and radiotherapy.

Routine antenatal anti-D prophylaxis for RhD-negative women: a systematic review and economic evaluation.

OBJECTIVES: To identify any evidence for advances in the use of routine antenatal anti-D prophylaxis (RAADP) since the 2002 National Institute for Health and Clinical Excellence (NICE) appraisal, and to assess the current clinical effectiveness and cost-effectiveness of RAADP for Rhesus D (RhD)-negative women. DATA SOURCES: Main bibliographic databases were searched from inception to July 2007. REVIEW METHODS: Selected studies were assessed and data extracted using a standard template and quality assessment based on published criteria. Meta-analysis was used where appropriate, otherwise outcomes were tabulated and discussed within a descriptive synthesis. The health economic model developed for the 2002 NICE appraisal of RAADP was modified to assess the cost-effectiveness of different regimens of RAADP. RESULTS: The clinical effectiveness searches identified 670 potentially relevant articles. Of these, 12 papers were included in the review, relating to eight studies of clinical effectiveness. With one exception, no additional studies were identified in comparison with the previous assessment report, and some of the studies of clinical effectiveness included in the 2002 review had to be excluded because they did not use currently licensed doses. Therefore, eight studies comparing RAADP with no prophylaxis were identified in the clinical effectiveness review and nine (including the 2001 assessment report itself) in the cost-effectiveness review. The clinical efficacy studies were generally of poor quality and did not provide a basis for differentiating between regimens of RAADP. The best indication of the likely efficacy of a programme of RAADP comes from two non-randomised community-based studies. The pooled results of these suggest that such a programme may reduce the sensitisation rate from 0.95% (95% CI 0.18-1.71) to 0.35% (95% CI 0.29-0.40). This gives an odds ratio for the risk of sensitisation of 0.37 (95% CI 0.21-0.65) and an absolute reduction in risk of sensitisation in RhD-negative mothers at risk (i.e. carrying a RhD-positive child) of 0.6%. The identified studies suggest that RAADP has minimal adverse effects. Of the nine studies in the cost-effectiveness review, only two described a model that could be applicable to the NHS. The economic model modified from the 2002 appraisal suggests that the cost per quality-adjusted life-year (QALY) gained of RAADP given to RhD-negative primigravidae versus no treatment is between 9000 pounds and 15,000 pounds, and for RAADP given to all RhD-negative women rather than to RhD-negative primigravidae only is between 20,000 pounds and 35,000 pounds depending upon the regimen. The sensitivity analysis suggests that the results are reasonably robust to changes in the assumptions within the model. CONCLUSIONS: RAADP reduces the incidence of sensitisation and hence of haemolytic disease of the newborn. The economic model suggests that RAADP given to all RhD-negative pregnant women is likely to be cost-effective at a threshold of around 30,000 pounds per QALY gained. The total cost of providing RAADP to RhD-negative primigravidae in England and Wales is estimated to be around 1.8-3.1 million pounds per year, depending upon regimen, and to all RhD-negative pregnant women in England and Wales around 2-3.5 million pounds.

Modelling the cost-effectiveness and capacity impact of changes to colposcopy referral guidelines for women with mild dyskaryosis in the UK Cervical Screening Programme.

OBJECTIVE: To evaluate the capacity implications and health economic impact of new guidelines recommending referral to colposcopy after one mild result during cervical screening rather than after two consecutive mild results. DESIGN: A mathematical model of the country's colposcopy services and the clinical pathways from smear result through to treatment is constructed. The model incorporates national questionnaire data on referral numbers and management practices, routine data and published research results. SETTING: All English NHS colposcopy services. POPULATION: Women aged 25 to 64 years. METHODS: The national average workload impact of the change in referral guidelines is predicted, and the impact in differing local circumstances is evaluated within the model. A long-term health economic model examines the resulting costs and predicted change in quality-adjusted life years (QALYs). MAIN OUTCOME MEASURES: Colposcopy workload implications for single mild dyskaryosis referral and cost per QALY analysis. RESULTS: We found that single mild dyskaryosis referral implies, on average, a 21% increase in colposcopy workload for services not currently operating this policy. The health economic model predicted a cost per QALY gained as a result of the implementation of the new referral guidelines of around pound7,500. CONCLUSIONS: Referral after one mild result will increase workload at colposcopy; however, it may be possible to counterbalance the additional workload by altering other clinical practice. The change to referral guidelines would be considered cost-effective in comparison with many interventions routinely available on the NHS.

Antiviral activity of Inonotus hispidus.

The antiviral activity of two phenolic compounds, hispolon and hispidin, isolated from the fruit bodies of the basidiomycete Inonotus hispidus as well as of some extracts prepared from fruit bodies and mycelial cultures of this fungus was investigated in allantois on the shell-test system. Ethanolic extracts, hispidin and hispolon showed considerable antiviral activity against influenza viruses type A and B.

Factors associated with outcome of cognitive-behavioural treatment of chronic post-traumatic stress disorder.

The study examined factors that were associated with outcome in the treatment of PTSD. A trial of cognitive therapy compared to imaginal exposure of chronic PTSD showed that although clinical improvements were obtained after treatment and at 6 month follow-up one type of treatment was not significantly superior to the other. Characteristics of the patient, the trauma and treatment and of pretreatment clinical measures were investigated as predictors of PTSD outcome. Eleven variables were significantly associated with the pre- to post-treatment change in CAPS severity scores. Of these, three (duration of therapy, gender and suicide risk) were selected into a step-wise multiple regression equation to explain 36.5% of the outcome. Similarly, nine variables were significant associated with the pretreatment to follow-up change with three variables (number of missed therapy sessions, residential status and co-morbid GAD) being selected into the equation and explaining 36.9% of the outcome. The best predictor of outcome was inconsistent attendance at therapy.

Relatives' expressed emotion (EE) and PTSD treatment outcome.

BACKGROUND: Expressed emotion (EE) is a measure that has been used to assess the quality of the relationship between patient and their key relative. It has been shown to be strongly predictive of clinical outcome in a range of psychiatric and medical disorders. This study investigated the effect of EE on treatment outcome in chronic post-traumatic stress disorder (PTSD). METHODS: A prospective design was adopted. The key relatives of 31 PTSD patients participating in a treatment trial comparing imaginal exposure with cognitive therapy were interviewed and rated on EE prior to treatment allocation. The effect of EE on post-treatment clinical outcomes was assessed. RESULTS: Sixteen patients (52%) had high EE and 15 (48%) low EE relatives. Patients with high EE relatives showed lesser change scores on the main outcome variable of the trial, the total CAPS score, and on all the secondary outcome variables than those with low EE relatives. Using different multiple regression models the EE scales of criticism and hostility predicted just under 20% of the outcome variance. These two scales were highly correlated and criticism marginally predicted the greatest variance (19.7%). CONCLUSIONS: The results highlight the importance of the quality of the patient's social environment in influencing their response to cognitive and behavioural treatments.

A randomized trial of cognitive therapy and imaginal exposure in the treatment of chronic posttraumatic stress disorder.

A randomized trial was performed in which imaginal exposure (IE) and cognitive therapy (CT) were compared in the treatment of chronic posttraumatic stress disorder (PTSD). Patients who continued to meet PTSD caseness at the end of a 4-week symptom-monitoring baseline period (n = 72) were randomly allocated to either IE or CT. There was a significant improvement in all measures over treatment and at follow-up, although there were no significant differences between the 2 treatments at any assessment. A significantly greater number of patients who showed worsening over treatment received IE, although this effect was not found at follow-up. Patients who worsened showed a greater tendency to miss treatment sessions, rated therapy as less credible, and were rated as less motivated by the therapist. It was concluded that either exposure or a challenge to cognition can result in symptom reduction, although neither resulted in complete improvement.

Cognitive therapy or imaginal exposure in the treatment of post-traumatic stress disorder. Twelve-month follow-up.

BACKGROUND: Previously reported results have demonstrated the efficacy of exposure and cognitive therapy in the treatment of chronic post-traumatic stress disorder (PTSD), but have not shown one to be superior to the other. AIMS: To investigate whether treatment benefits and equivalence are maintained at 12-month follow-up in patients with chronic PTSD treated with either imaginal exposure or cognitive therapy. METHOD: Twelve-month follow-up of a randomised clinical trial. RESULTS: Fifty-four subjects (87% of the sample) were available to follow-up. They did not significantly differ clinically from drop-outs. There was significant clinical improvement at 12 months compared with pre-treatment. However, 39% of those followed-up still met criteria for PTSD. There were no significant differences between the two treatments. Victims of crime displayed higher levels of symptoms at follow-up than victims of accidents. CONCLUSIONS: Clinical benefits for exposure or cognitive therapy were maintained.

Inhibition of chemiluminescence response of human mononuclear cells and suppression of mitogen-induced proliferation of spleen lymphocytes of mice by hispolon and hispidin.

The effects of two phenolic compounds, hispolon and hispidin isolated from fruit bodies of the basidiomycete Inonotus hispidus (Bull. ex Fr.) Karst, were investigated on the chemiluminescence response by LPS- or zymosan-activated human mononuclear cells (MNC) and on the concanavalin A-induced proliferation of spleen lymphocytes of mouse in vitro. Both compounds showed inhibitory activity in the chemiluminescence-test with an IC50 (the concentration of test compound causing 50% effect) ranging from 4.4 to 4.6 micrograms/ml (20.3 to 21.2 microM) for hispolon and < 0.1 to 1.5 micrograms/ml (from < 0.4 microM to 6.0 microM) for hispidin. Antiproliferative effects have been achieved in the lymphocyte transformation test (LTT) by hispolon with an IC50 of 3.4 micrograms/ml (15.5 microM).

[Trypsin inhibitor activity in Basidiomycetes]. / Trypsininhibitoraktivität in Basidiomyceten.

46 species of 10 families of basidiomycetes were screened for trypsin-inhibitor activity. These mushrooms were extracted with water to estimate the inhibitor activity. High inhibitor activity (trypsin inhibition higher than 50%) was estimated in 8 species of 5 families.

[The inhibition of endothelial cell proliferation by esters of 4-aminomethylbenzoic acid (pamba)]. / Die Hemmung der Endothelzellproliferation durch Ester der 4-Aminomethylbenzoesäure (PAMBA).

PAMBA-esters are able to decrease the proliferation of in vitro cultivated endothelial cells. PAMBA-hexylester was found to be the most effective one. In comparison to PAMBA-ethylester the ethylesters of EACA, 4-amino-benzoic acid, 4-amidinobenzoic acid and 4-amidino-phenylpyruvic acid were investigated.

Inhibition of cell migrations by the linoleic acid oxygenation product 9S-hydroxy 10E,12Z octadecadienoic acid (9-HODE).

The linoleic acid metabolite 9S-HODE was prepared by means of tomato fruit lipoxygenase and purified by high-performance liquid chromatography (HPLC) to a high steric purity as judged by chiral-phase HPLC. 9S-HODE caused in the concentration range between 0.01 and 1 microM a strong dose-dependent inhibition of the migration of both cultured porcine aortic endothelial cells and of phytohaemagglutinin-stimulated human mononuclear cells. The effect was not observed with another polyenoic fatty acid metabolite, 15S-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15-HPETE). The results are discussed in the light of other biological actions of 9-HODE recently described.