No socioeconomic inequalities in ovarian cancer survival within two randomised clinical trials.

BACKGROUND: Ovarian cancer is the leading cause of death among cancers of the female genital tract, with poor outcomes despite chemotherapy. There was a persistent socioeconomic gradient in 1-year survival in England and Wales for more than 3 decades (1971-2001). Inequalities in 5-year survival persisted for more than 20 years but have been smaller for women diagnosed around 2000. We explored one possible explanation. METHODS: We analysed data on 1406 women diagnosed with ovarian cancer during 1991-1998 and recruited to one of two randomised clinical trials. In the second International Collaborative Ovarian Neoplasm (ICON2) trial, women diagnosed between 1991 and 1996 were randomised to receive either the three-drug combination cyclophosphamide, doxorubicin and cisplatin (CAP) or single-agent carboplatin given at optimal dose. In the ICON3 trial, women diagnosed during 1995-1998 were randomised to receive either the same treatments as ICON2, or paclitaxel plus carboplatin.Relative survival at 1, 5 and 10 years was estimated for women in five categories of socioeconomic deprivation. The excess hazard of death over and above background mortality was estimated by fitting multivariable regression models with Poisson error structure and a dedicated link function in a generalised linear model framework, adjusting for the duration of follow-up and the confounding effects of age, Federation of Gynecology and Obstetrics (FIGO) stage and calendar period. RESULTS: Unlike women with ovarian cancer in the general population, no statistically significant socioeconomic gradient was seen for women with ovarian cancer treated in the two randomised controlled trials. The deprivation gap in 1-year relative survival in the general population was statistically significant at -6.7% (95% CI (-8.1, -5.3)), compared with -3.6% (95% CI (-10.4, +3.2)) in the trial population. CONCLUSIONS: Although ovarian cancer survival is significantly lower among poor women than rich women in England and Wales, there was no evidence of an association between socioeconomic deprivation and survival among women with ovarian cancer who were treated and followed up consistently in two well-conducted randomised controlled trials. We conclude that the persistent socioeconomic gradient in survival among women with ovarian cancer, at least for 1-year survival, may be due to differences in access to treatment and standards of care.

A high resolution ultraviolet Brillouin scattering set-up.

We report on a high resolution inelastic UV scattering table-top setup conceived for Brillouin measurements. The system is based on a tandem 1+1 pass scanning Fabry-Perot interferometer of Sandercock type. Special optics were used in order to adapt such an interferometric device, nowadays only used at visible or IR wavelength, to the UV range. The advantages with respect to other UV Brillouin scattering instruments are the larger resolving power and the improved contrast in the low frequency spectral region. To corroborate these features we provide a comparison between data obtained using the described system and those from existing UV Brillouin scattering instruments.

Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.

OBJECTIVES: To systematically review the effectiveness and cost-effectiveness of palivizumab for the prevention of respiratory syncytial virus (RSV) in children and examine prognostic factors to determine whether subgroups can be identified with important differences in cost-effectiveness. DATA SOURCES: Bibliographic databases were searched from inception to March 2007 for literature on the effectiveness and cost-effectiveness of prophylaxis with palivizumab. REVIEW METHODS: The literature was systematically reviewed and current economic evaluations were analysed to identify which parameters were driving the different cost-effectiveness estimates. A probabilistic decision-analytical model was built to assess the cost-effectiveness of prophylaxis with palivizumab for children at risk of RSV infection and the parameters populated with the best estimates thought most applicable to the UK. We also constructed a new model, the Birmingham Economic Evaluation (BrumEE). Cost-effectiveness analyses were undertaken from both NHS and societal perspectives. RESULTS: Two randomised controlled trials (RCTs) were identified. Prophylaxis with palivizumab for preterm infants without chronic lung disease (CLD) or children with CLD resulted in a 55% reduction in RSV hospital admission: 4.8% (48/1002) in the palivizumab group and 10.6% (53/500) in the no prophylaxis group (p = 0.0004). Prophylaxis with palivizumab was associated with a 45% reduction in hospitalisation rate RSV among children with coronary heart disease (CHD). Hospitalisation rates for RSV were 5.3% (34/639) in the palivizumab group and 9.7% (63/648) in the no prophylaxis group (p = 0.003). Of existing economic evaluations, 3 systematic reviews and 18 primary studies were identified. All the systematic reviews concluded that the potential costs of palivizumab were far in excess of any potential savings achieved by decreasing hospital admission rates, and that the use of palivizumab was unlikely to be cost-effective in all children for whom it is recommended, but that its continued use for particularly high-risk children may be justified. The incremental cost-effectiveness ratios (ICERs) of the primary studies varied 17-fold for life-years gained (LYG), from 25,800 pounds/LYG to 404,900 pounds/LYG, and several hundred-fold for quality-adjusted life-years (QALYs), from 3200 pounds/QALY to 1,489,700 pounds/QALY for preterm infants without CLD or children with CLD. For children with CHD, the ICER varied from 5300 pounds/LYG to 7900 pounds/LYG and from 7500 pounds/QALY to 68,700 pounds/QALY. An analysis of what led to the discrepant ICERs showed that the assumed mortality rate for RSV infection was the most important driver. The results of the BrumEE confirm that palivizumab does not reach conventional levels of cost-effectiveness in any of the licensed indications if used for all eligible children. CONCLUSIONS: Prophylaxis with palivizumab is clinically effective for the reducing the risk of serious lower respiratory tract infection caused by RSV infection and requiring hospitalisation in high-risk children, but if used unselectively in the licensed population, the ICER is double that considered to represent good value for money in the UK. The BrumEE shows that prophylaxis with palivizumab may be cost-effective (based on a threshold of 30,000 pounds/QALY) for children with CLD when the children have two or more additional risk factors. Future research should initially focus on reviewing systematically the major uncertainties for patient subgroups with CLD and CHD and then on primary research to address the important uncertainties that remain.

A systematic review and economic evaluation of epoetin alpha, epoetin beta and darbepoetin alpha in anaemia associated with cancer, especially that attributable to cancer treatment.

OBJECTIVES: To assess the effectiveness and cost-effectiveness of epoetin alpha, epoetin beta and darbepoetin alpha (referred to collectively in this report as epo) in anaemia associated with cancer, especially that attributable to cancer treatment. DATA SOURCES: Electronic databases were searched from 2000 (1996 in the case of darbepoetin alpha) to September 2004. REVIEW METHODS: Using a recently published Cochrane review as the starting point, a systematic review of recent randomised controlled trials (RCTs) comparing epo with best standard was conducted. Inclusion, quality assessment and data abstraction were undertaken in duplicate. Where possible, meta-analysis was employed. The economic assessment consisted of a systematic review of past economic evaluations, an assessment of economic models submitted by the manufacturers of the three epo agents and development of a new individual sampling model (the Birmingham epo model). RESULTS: In total 46 RCTs were included within this systematic review, 27 of which had been included in the Cochrane systematic review. All 46 trials compared epo plus supportive care for anaemia (including transfusions), with supportive care for anaemia (including transfusions), alone. Haematological response (defined as an improvement by 2 g/dl(-1)) had a relative risk of 3.4 [95% confidence interval (CI) 3.0 to 3.8, 22 RCTs] with a response rate for epo of 53%. The trial duration was most commonly 16-20 weeks. There was little statistical heterogeneity in the estimate of haematological response, and there were no important differences between the subgroups examined. Haemoglobin (Hb) change showed a weighted mean difference of 1.63 g/dl(-1) (95% CI 1.46 to 1.80) in favour of epo. Treatment with erythropoietin in patients with cancer-induced anaemia reduces the number of patients who receive a red blood cell transfusion (RBCT) by an estimated 18%. Health-related quality of life (HRQoL) data were analysed using vote counting and qualitative assessment and a positive effect was observed in favour of an improved HRQoL for patients on epo. Published information on side-effects was of poor quality. New trials provided further evidence of side-effects with epo, particularly thrombic events, but it is still unclear whether these could be accounted for by chance alone. The results of the previous Cochrane review had suggested a survival advantage for epo (HR 0.84, 95% CI 0.69 to 1.02), based on 19 RCTs. The update, based on 28 RCTs, suggests no difference (HR 1.03, 95% CI 0.88 to 1.21). Subgroup analysis suggested some explanations for this heterogeneity, but it is difficult to draw firm conclusions without access to the substantial amounts of missing or unpublished data, or more detailed results from some of the trials with heterogeneous patient populations. The conclusions are, however, broadly in line with those of a Food and Drug Administration (FDA) safety briefing, which recommended that patients with a haemoglobin above 12 g/dl(-1) should not be treated; the target rate of rise in Hb should not be too great, and further carefully conducted trials are required to determine which subgroups of patients may be harmed by the use of these products, in particular through the stimulation of tumour activity. Five published economic evaluations identified from the literature had inconsistent results, with estimates ranging from a cost per quality-adjusted life-year (QALY) under pound 10,000 through to epo being less effective and more costly than standard care. The more favourable evaluations assumed a survival advantage for epo. The three company models submitted each relied on assumed survival gains to achieve relatively low cost per QALY, from pound 13,000 to pound 28,000, but generated estimates from pound 84,000 to pound 159,000 per QALY when no survival gain was assumed. Each of these models relied on Hb levels alone driving utility, and each assumed gradual normalisation of Hb in the standard treatment arm after the end of treatment. The Birmingham epo model followed the company models in regard to the relationship between Hb levels and utility, and also assumed normalisation in the base case. With no survival gain, the incremental cost per QALY was pound 150,000, falling to pound 40,000 when the lower, more favourable, confidence interval for survival was used. CONCLUSIONS: Epo is effective in improving haematological response and reducing RBCT requirements, and appears to have a positive effect on HRQoL. The incidence of side-effects and effects on survival remains highly uncertain. However, if there is no impact on survival, it seems highly unlikely that epo would be considered a cost-effective use of healthcare resources. The main target for further research should be improving estimates of impact on survival, initially through more detailed secondary research, such as the individual patient data meta-analysis started by the Cochrane group. Further trials may be required, and have been recommended by the FDA, although many trials are in progress, completed but unreported or awaiting mature follow-up. The Birmingham epo model developed as part of this project contains new features that improve its flexibility in exploring different scenarios; further refinement and validation would therefore be of assistance. Finally, further research to resolve uncertainty about other parameters, particularly quality of life, adverse events, and the rate of normalisation, would also be beneficial.

Erythropoietin or darbepoetin for patients with cancer.

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (Epo), darbepoetin (Darbepo) and red blood cell transfusions. OBJECTIVES: The aim of this systematic review was to assess the effects of Epo or Darbepo to either prevent or treat anaemia in cancer patients. SEARCH STRATEGY: We searched the Central Register of Controlled Trials, MEDLINE and EMBASE and other data bases. Searches were done for the periods 01/1985 to 12/2001 for the first review and 1/2002 to 04/2005 for the update. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials on managing anaemia in cancer patients that compared the use of Epo/Darbepo (plus transfusion if needed) with observation until red blood cell transfusion was required. DATA COLLECTION AND ANALYSIS: Several reviewers independently assessed trial quality and extracted data. MAIN RESULTS: This update of the systematic review included a total of 57 trials with 9,353 patients. Of these, 27 trials with 3,287 adults were also included in the first Cochrane Review. Thirty trials with 6,066 patients were added during the update process. Use of Epo/Darbepo significantly reduced the relative risk of red blood cell transfusions (RR 0.64; 95% CI 0.60 to 0.68, 42 trials, n = 6,510). On average participants in the Epo/Darbepo group received one unit of blood less than the control group (WMD -1.05; 95% CI -1.32 to -0.78, 14 trials, n = 2,353). For participants with baseline haemoglobin below 12 g/dL haematological response was observed more often in participants receiving Epo/Darbepo (RR 3.43; 95% CI 3.07 to 3.84, 22 trials, n = 4,307). There was suggestive evidence that Epo/Darbepo may improve Quality of Life (QoL). The relative risk for thrombo embolic complications was increased in patients receiving Epo/Darbepo compared to controls (RR 1.67, 95% CI 1.35 to 2.06; 35 trials, n = 6,769). Uncertainties remain whether and how Epo/Darbepo effects tumour response (fixed effect RR 1.12; 95% CI 1.01 to 1.23, 13 trials, n = 2,833; random effects: RR 1.09; 95% CI 0.94 to 1.26) or overall survival (unadjusted and adjusted data: HR 1.08; 95% CI 0.99 to 1.18; 42 trials, n = 8,167). AUTHORS' CONCLUSIONS: There is consistent evidence that administration of Epo/Darbepo reduces the relative risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 12 g/dL (mild anaemia) there is strong evidence that Epo/Darbepo improves haematological response. There is suggestive evidence that Epo/Darbepo may improve QoL. However, there is strong evidence that Epo/Darbepo increases the relative risk for thrombo embolic complications. Whether and how Epo/Darbepo effects tumour response and overall survival remains uncertain.

The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of newer antiepileptic drugs (AEDs) for epilepsy in children: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin. DATA SOURCES: Electronic databases. Drug company submissions. REVIEW METHODS: For the systematic review of clinical and cost-effectiveness, studies were assessed for inclusion according to predefined criteria. Data extraction and quality assessment were also undertaken. A decision-analytic model was constructed to estimate the cost-effectiveness of the newer agents in children with partial seizures, the only condition where there were sufficient trial data to inform a model. RESULTS: The quality of the randomised controlled trial (RCT) data was generally poor. For each of the epilepsy subtypes considered in RCTs identified for this review (partial epilepsy with or without secondary generalisation, Lennox-Gastaut syndrome, infantile spasms, absence epilepsy and benign epilepsy with centrotemporal spikes), there is some evidence from placebo-controlled trials that the newer agents tested are of some value in the treatment of these conditions. Where active controls have been used, the limited evidence available does not indicate a difference in effectiveness between newer and older drugs. The data are not sufficient to inform a prescribing strategy for any of the newer agents in any of these conditions. In particular, there is no clinical evidence to suggest that the newer agents should be considered as a first-choice treatment in any form of epilepsy in children. Annual drug costs of the newer agents ranges from around 400 pound to 1200 pound, depending on age and concomitant medications. An AED that is ineffective or has intolerable side-effects will only be used for a short period of time, and many patients achieving seizure freedom will successfully withdraw from drug treatment without relapsing. The results of the decision-analytic model do not suggest that the use of the newer agents in any of the scenarios considered is clearly cost-effective but, similarly, do not indicate that they are clearly not cost-effective. CONCLUSIONS: The prognosis for children diagnosed with epilepsy is generally good, with a large proportion responding well to the first treatment given. A substantial proportion, however, will not respond well to treatment, and for these patients the clinical goal is to find an optimal balance between the benefits and side-effects of any treatment given. For the newly, or recently, diagnosed population, the key question for the newer drugs is how soon they should be tried. The cost-effectiveness of using these agents early, in place of one of the older agents, will depend on the effectiveness and tolerability of these agents compared with the older agents; the evidence from the available trial data so far suggests that the newer agents are no more effective but may be somewhat better tolerated than the older agents, and so the cost-effectiveness for early use will depend on the trade-off between effectiveness and tolerability, both in terms of overall (long-term) treatment retention and overall utility associated with effects on seizure rate and side-effects. There are insufficient data available to estimate accurately the nature of this trade off either in terms of long-term treatment retention or utility. Better information is required from RCTs before any rational evidence-based prescribing strategy could be developed. Ideally, RCTs should be conducted from a 'public health' perspective, making relevant comparisons and incorporating outcomes of interest to clinicians and patients, with sufficiently long-term follow-up to determine reliably the clinical utility of different treatments, particularly with respect to treatment retention and the balance between effectiveness and tolerability. RCTs should mirror clinical practice with respect to diagnosis, focusing on defined syndromes or, where no syndrome is identified, on groups defined by specific seizure type(s) and aetiology. Epilepsy in children is a complex disease, with a variety of distinct syndromes and many alternative treatment options and outcomes. Diagnosis-specific decision-analytic models are required; further research may be required to inform parameter values adequately with respect to epidemiology and clinical practice.

The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

OBJECTIVES: To assess the clinical and cost-effectiveness of parent training programmes for the treatment of children with conduct disorder (CD) up to the age of 18 years. DATA SOURCES: Electronic databases. REVIEW METHODS: For the effectiveness review, relevant studies were identified and evaluated. A quantitative synthesis of behavioural outcomes across trials was also undertaken using two approaches: vote counting and meta-analysis. The economic analysis consisted of reviewing previous economic/cost evaluations of parent training/education programmes and the economic information within sponsor's submissions; carrying out a detailed exploration of costs of parent training/education programmes; and a de novo modelling assessment of the cost-effectiveness of parent training/education programmes. The potential budget impact to the health service of implementing such programmes was also considered. RESULTS: Many of the 37 randomised controlled trials that met the review inclusion and exclusion criteria were assessed as being of poor methodological quality. Studies were clinically heterogeneous in terms of the population, type of parent training/education programme and content, setting, delivery, length and child behaviour outcomes used. Both vote counting and meta-analysis revealed a consistent trend across all studies towards short-term effectiveness (up to 4 months) of parent training/education programmes (compared with control) as measured by a change in child behaviour. Pooled estimates showed a statistically significant improvement on the Eyberg Child Behaviour Inventory frequency and intensity scales, the Dyadic Parent-Child Interaction Coding System and the Child Behaviour Checklist. No studies reported a statistically significant result favouring control over parent training/education programmes. There were few statistically significant differences between different parent training/education programmes, although there was a trend towards more intensive interventions (e.g. longer contact hours, additional child involvement) being more effective. The cost of treating CD is high, with costs incurred by many agencies. A recent study suggested that by age 28, costs for individuals with CD were around 10 times higher than for those with no problems, with a mean cost of 70,019 pounds sterling. Criminality incurs the greatest cost, followed by educational provision, foster and residential care and state benefits. Only a small proportion of these costs fall on health services. Using a 'bottom-up' costing approach, the costs per family of providing parent training/education programmes range from 629 pounds sterling to 3839 pounds sterling depending on the type and style of delivery. Using the conservative assumption that there are no cost savings from treatment, a total lifetime quality of life gain of 0.1 would give a cost per quality-adjusted life-year of between 38,393 pounds sterling and 6288 pounds sterling depending on the type of programme delivery and setting. CONCLUSIONS: Parent training/education programmes appear to be an effective and potentially cost-effective therapy for children with CD. However, the relative effectiveness and cost-effectiveness of different models (such as therapy intensity and setting) require further investigation. Further research is required on the impact of parent training/education programmes on the quality of life of children with CD and their parents/carers, as well as on longer term child outcomes.

Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

OBJECTIVES: To determine the role of autoantibody tests for autoimmune diseases in children with newly diagnosed type 1 diabetes mellitus. DATA SOURCES: MEDLINE, EMBASE and the Cochrane Library. Citation lists of included studies were scanned and relevant professional and patient websites reviewed. Laboratories and manufacturers were contacted to identify ongoing or unpublished research. REVIEW METHODS: Following scoping searches on thyroid and coeliac autoantibodies, a systematic review of autoantibody tests for diagnosis of coeliac disease was carried out. Studies were included where cohorts of untreated patients with unknown disease status were included, all patients had undergone the reference test (biopsy) and antibody tests, and sensitivity and specificity were reported or calculable. Selected studies were then evaluated against a quality checklist. Summary statistics of diagnostic accuracy, i.e. sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratios, were calculated for all studies. A decision analytic model was developed to evaluate the cost utility of screening for coeliac disease at diagnosis of diabetes. RESULTS: All antibody tests for diagnosis of coeliac disease showed reasonably good diagnostic test accuracy. Studies reported variable measures of test accuracy, which may be due to aspects of study quality, differences in the tests and their execution in the laboratories, different populations and reference standards. The decision analytic model indicated screening for coeliac disease at diagnosis of diabetes was cost-effective. Sensitivity analyses exploring variations in the cost and disutility of gluten-free diet, the utilities attached to treated and untreated coeliac disease and the decrease in life expectancy associated with treated and untreated coeliac disease did substantially affect the cost-effectiveness of the screening strategies considered. CONCLUSIONS: In terms of test accuracy in testing for coeliac disease, immunoglobulin A (IgA) anti-endomysium is the most accurate test. If an enzyme-linked immunoassay test was required, which may be more suitable for screening purposes as it can be semi-automated, testing for IgA tissue transglutaminase is likely to be most accurate. The decision analytic model shows that the most accurate tests combined with confirmatory biopsy are the most cost-effective, whilst combinations of tests add little or no further value. There is limited information regarding test accuracy in screening populations with diabetes, and there is some uncertainty over whether the test characteristics would remain the same. Further research is required regarding the role of screening in silent coeliac disease and regarding long-term outcomes and complications of untreated coeliac disease.

Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids in trauma patients.

OBJECTIVES: To systematically review the evidence on the effectiveness (in terms of mortality and morbidity) of prehospital intravenous (i.v.) fluid replacement, compared with no i.v. fluid replacement or delayed fluid replacement, in trauma patients with no head injury who have haemorrhage-induced hypotension due to trauma. DATA SOURCES: Electronic databases, relevant websites, handsearching, expert contacts. REVIEW METHODS: Search strategies were defined to identify randomised controlled trials (RCTs) and previous systematic reviews relating to the use of i.v. fluids in a prehospital (or other) setting compared to no fluids or delayed fluids. Inclusion and exclusion criteria were applied to identified studies, and key quality criteria of included studies were checked. Data were extracted independently by two reviewers. Economic evaluations were also systematically sought and appraised. RESULTS: Four relevant RCTs were identified, three of which were poorly designed and/or conducted. One good-quality RCT suggested that i.v. fluids may be harmful in patients with penetrating injuries. No evidence was found on the relative effectiveness of i.v. fluids in patients with blunt versus penetrating trauma. No reliable evidence was found from systematic reviews to suggest that a particular type of fluid is more beneficial compared to another type, although there was a trend favouring crystalloids over colloids. The relative costs of using i.v. fluids versus not using them were found to be very similar and changes in the use of fluids would therefore have no cost consequences for the ambulance service. A more detailed cost-effectiveness analysis would require further information on the relative consequences (mortality, morbidity) of different resuscitation strategies. CONCLUSIONS: The review found no evidence to suggest that prehospital i.v. fluid resuscitation is beneficial, and some evidence that it may be harmful. This evidence is however not conclusive, particularly for blunt trauma. A UK Consensus Statement, and to a lesser extent the UK Joint Royal Colleges Ambulance Liaison Committee guidelines represent a more cautious approach to fluid management than previously advocated and are therefore consistent with the limited evidence base. Further research is required on hypotensive (cautious) resuscitation versus delayed or no fluid replacement, particularly in blunt trauma. There is also a need for an improvement in the quality of data collection and analysis of routinely collected ambulance call-out data.

First-line treatment for advanced ovarian cancer: paclitaxel, platinum and the evidence.

Four large randomised trials of paclitaxel in combination with platinum against a platinum-based control treatment have now been published in full, representing around 88% (3588 out of 4057) of patients randomised into the eight known trials of this question. There is substantial heterogeneity in the results of these four trials. Four main explanations for this heterogeneity have been proposed: differences in the extent and timing of 'crossover' to taxanes in the control groups; differences in the types of patient included; differences in the effectiveness of the research regimens used; differences in the effectiveness of the control regimens used. In this study we examine whether any of these explanations is consistent with the pattern of results seen in these trials. Each explanation suggests that a particular characteristic of each trial was responsible for the results observed. For each explanation the trials were split into groups according to that characteristic, in order to partition the total heterogeneity into that seen 'within' and 'between' groups of trials. If a particular explanation was consistent with the pattern of results, we would expect to see relatively little heterogeneity within each group of trial results viewed in this way, with most of the heterogeneity being between groups which are dissimilar with respect to the key characteristic. Heterogeneity 'within' and 'between' groups was formally compared using the F-ratio. If any explanation appeared to be consistent with the results of the trials, it was considered whether the explanation was also consistent with other evidence available about these regimens. Only one explanation appeared to be consistent with the pattern of results seen in these trials, and that was differences in effectiveness of the control arms used in these trials. This suggests that the very positive results in favour of paclitaxel/cisplatin seen in two of the trials may have been due to the use of a suboptimal control arm. There is no direct evidence about the relative effectiveness of the control arms used in these trials, but indirect evidence is consistent with the conclusion that the cyclophosphamide/cisplatin regimen used in two of the trials may be less effective than the control regimens used in the other trials. Specific concerns about the choice of a cyclophosphamide/cisplatin control arm in the first of these trials to report were raised before the results of the other trials were known, i.e. before any heterogeneity had been observed. Further investigation of this question would be useful. In the meantime, given all of the randomised evidence on the efficacy and toxicity associated with the regimens used in these trials, we conclude that single agent carboplatin is a safe and effective first-line treatment for women with advanced ovarian cancer.

First-line chemotherapy for advanced ovarian cancer: paclitaxel, cisplatin and the evidence.

As of June 1998, four randomized trials have been completed comparing the combination of paclitaxel and cisplatin with a cisplatin-based control arm. The results of three of these trials are available; one has been published as a full paper, the other two in abstract form only. Two of the reported trials (GOG-111 and the Intergroup trial) provide clear evidence that cisplatin combined with paclitaxel is a more effective regimen than one using the same dose of cisplatin combined with cyclophosphamide. The results of the third reported trial (GOG-132) are rather different, suggesting that a higher dose of single-agent cisplatin may be as effective as the paclitaxel/cisplatin combination tested in the other two trials. A number of explanations for these unexpected results have been proposed: false-positive results in GOG-111 and the Intergroup trial; false-negative results in GOG-132; high crossover in GOG-132 (including crossover before progression); the cyclophosphamide in the control arm of GOG-111 and the Intergroup trial had a negative impact on outcome in the control group in these trials; the higher dose of cisplatin when used as a single agent in GOG-132 had a positive impact on outcome for the control group in this trial. These explanations are discussed in detail, and their implications explored.

Analysis of the major domains of the F fertility inhibition protein, FinO.

The mechanism of fertility inhibition of conjugation by the F plasmid depends on the presence of both the FinO protein and an antisense RNA, FinP, which together control the expression of the positive regulator of the transfer operon TraJ. FinO both prevents the degradation of FinP, allowing its intracellular concentration to rise, and promotes duplex formation with its target, the traJ mRNA. In this study, deletions in finO were constructed and fused to gst, encoded by the pGEX-2T expression vector, to give GST-FinO fusions of varying lengths. These fusions were then tested for their ability to bind FinP and traJ mRNA, and to promote duplex formation. Our results suggest that the predicted basic N-terminal alpha-helix is involved in RNA binding, while the central domain is involved in duplex formation. The presence of the acidic C-terminal domain protects FinP from ribonucleolase degradation and might enhance binding of the N-terminal alpha-helical domain in a manner reminiscent of the Rom protein of ColE1.

The sensitivity of forensic tests for rape.

The objective of this study is to provide an overview of the types of forensic evidence gathered during clinical examinations in cases of sexual assault, and to review the literature regarding the sensitivity of individual procedures. The methodology involved a computerized literature search of the MEDLINE, PsycINFO, Cinahl and HealthStar databases from 1992 to 1996, and a secondary search involving consultation with local facilities and manual searching of reference lists. Based on our review, the chance of finding positive evidence is largely time-dependent, particularly regarding sperm and seminal products, which are weighted most heavily in rape investigations. The best chance of recovering seminal evidence is most frequently stated as being less than 50%, with far lower chances after 24 hours. Specific tests such as pubic hair combing would not be expected to yield evidence in more than 4% of cases. That test, while of low sensitivity, is at least not as invasive as some of the others. More invasive tests, such as sampling from the rectal cavity, yield positive sperm findings in fewer than 2% of cases. The importance of ensuring that those working in the field of sexual assault understand that no positive finding on forensic tests does not mean that no attack occurred is highlighted. Medico-legal implications are discussed and suggestions for future research initiatives are highlighted.

Risk assessments for acute violence to third parties: a review of the literature.

OBJECTIVES: To provide an overview of risk assessments for acute violence to third parties by combining a clinical and research focus and to offer guidelines to physicians conducting clinical assessments. METHOD: A computerized literature search of the MEDLINE and PSYCHINFO data bases from 1967 to 1996 was completed using the key words violence, aggression, dangerous behaviour, risk, risk assessment, risk factors, and practice guidelines. The search yielded 116 relevant references, 26 of which were original research articles on risk factor identification. A secondary search, based on the citations from the primary search, yielded an additional 8 general discussion articles. RESULTS: Risk assessments may be conducted using different methods, although all methods should be systematic and comprehensive. Research shows that risk assessments do have validity for use in short-term prediction and that it is possible to develop clinical guidelines in this area. A combined clinical and research approach holds the most promise for improving the accuracy of probability estimates, and most published guides and tools rely on such a combination. CONCLUSIONS: Risk assessments are an important and necessary part of the clinical examination. Because this field has sufficiently evolved, there is abundant literature to refer to when determining what constitutes an acceptable assessment for risk of violence to third parties and when it is appropriate to conduct such an examination.

Inverted tandem duplication generates a duplication deficiency of chromosome 8p.

An adult female with sever mental retardation and dysmorphic features is described. A de novo chromosomal aberration involving 8p was found. The karyotype was 46, XX, inv dup (8) (p12----p23.1). Dosage studies with the DNA probe D8S7, which is located at 8p23----8pter, showed that the patient was monosomic for this marker. Thus the de novo rearrangement generated a duplication-deficiency chromosome. The possible mechanisms of formation of this abnormal chromosome are discussed.