Allogeneic NK cells induce the in vitro activation of monocyte-derived and conventional type-2 dendritic cells and trigger an inflammatory response under cancer-associated conditions.

Natural killer (NK) cells are innate lymphocytes capable to recognize and kill virus-infected and cancer cells. In the past years, the use of allogeneic NK cells as anti-cancer therapy gained interest due to their ability to induce graft-versus-cancer responses without causing graft-versus-host disease and multiple protocols have been developed to produce high numbers of activated NK cells. While the ability of these cells to mediate tumor kill has been extensively studied, less is known about their capacity to influence the activity of other immune cells that may contribute to a concerted anti-tumor response in the tumor microenvironment (TME). In this study, we analyzed how an allogeneic off-the-shelf cord blood stem cell-derived NK-cell product influenced the activation of dendritic cells (DC). Crosstalk between NK cells and healthy donor monocyte-derived DC (MoDC) resulted in the release of IFNγ and TNF, MoDC activation, and the release of the T-cell-recruiting chemokines CXCL9 and CXCL10. Moreover, in the presence of prostaglandin-E2, NK cell/MoDC crosstalk antagonized the detrimental effect of IL-10 on MoDC maturation leading to higher expression of multiple (co-)stimulatory markers. The NK cells also induced activation of conventional DC2 (cDC2) and CD8+ T cells, and the release of TNF, GM-CSF, and CXCL9/10 in peripheral blood mononuclear cells of patients with metastatic colorectal cancer. The activated phenotype of MoDC/cDC2 and the increased release of pro-inflammatory cytokines and T-cell-recruiting chemokines resulting from NK cell/DC crosstalk should contribute to a more inflamed TME and may thus enhance the efficacy of T-cell-based therapies.

Women's views about breast cancer prevention at mammography screening units and well women's clinics.

Background: Women attending mammography screening units (msus) and well women's clinics (wwcs) represent a motivated cohort likely to engage in interventions aimed at primary breast cancer (bca) prevention. Methods: We used a feasibility questionnaire distributed to women (40-49 or 50-74 years of age) attending msus and wwcs in Halifax, Nova Scotia, to examine■ women's views about bca primary prevention and sources of health care information,■ prevalence of lifestyle-related bca risk factors, and■ predictors of prior mammography encounters within provincial screening guidelines.Variables examined included personal profiling, comorbidities, prior mammography uptake, lifestyle behaviours, socioeconomic status, health information sources, and willingness to discuss or implement lifestyle modifications, or endocrine therapy, or both. A logistic regression analysis examined associations with prior mammography encounters. Results: Of the 244 responses obtained during 1.5 months from women aged 40-49 years (n = 75) and 50-74 years (n = 169), 56% and 75% respectively sought or would prefer to receive health information from within, as opposed to outside, health care. Lifestyle-related bca risk factors were prevalent, and most women were willing to discuss or implement lifestyle modifications (93%) or endocrine therapy (67%). Of the two age groups, 49% and 93% respectively had previously undergone mammography within guidelines. Increasing age and marital status (single, separated, or divorced vs. married or partnered) were independent predictors of prior mammography encounters within guidelines for women 40-49 years of age; no independent predictors were observed in the older age group. Conclusions: Women attending msus and wwcs seem to largely adhere to mammography guidelines and appear motivated to engage in bca primary prevention strategies, including lifestyle modifications and endocrine therapy. Women's views as observed in this study provide a rationale for the potential incorporation of bca risk assessment within the "mammogram point of care" to engage motivated women in bca primary prevention strategies.

Cannabis use in pediatric cancer patients: what are they reading? A review of the online literature.

BACKGROUND: Recent changes to the legal status of marijuana in Canada warrant a review of the information that patients and families are accessing online regarding the role of cannabis in cancer. The aims of the current research were to identify the quality of literature available online as well as the themes, and opinion (i.e., pro-, neutral, or anti-cannabis) of online articles. METHODS: Searches were conducted using three primary search engines: Google, Yahoo, and DuckDuckGo. Articles were assessed for quality based on a modified scale for evaluating online sources. Content of all unique articles was coded using a qualitative thematic methodology in a line-by-line fashion. Codes were clustered to determine themes within articles. Finally, opinions were determined by examining all articles in a line-by-line fashion. Each statement was coded as either pro-cannabis (positive) or anti-cannabis (negative). RESULTS: We found most articles were authored by journalists (39.4%) and MDs (14.1%) and published as news (35.2%) or web articles (28.2%). The content of articles focused on four themes: the reasons for and against cannabis use; the opinions of health care providers; the restrictions placed by governing bodies and the need for additional research, education, and standardization. Article opinions were neutral-pro-cannabis. CONCLUSIONS: Health care providers should be aware that the overall quality of information found online is considered "satisfactory." The majority of articles present a pro-cannabis opinion.

Neo-antigen specific T cell responses indicate the presence of metastases before imaging.

Non-small cell lung cancer (NSCLC) causes 19% of all Australian cancer deaths, with a 5-year survival post-resection of around 60%. Post-operative recurrence is due to metastases that were undetectable pre-operatively, or growth of microscopic locoregional residual disease. However, post-operative imaging modalities typically only detect more advanced tumours; where PET-CT has a detection limit of 6-7 mm. Detection of small deposits of lung metastatic disease is of importance in order to facilitate early and potentially more effective treatment. In this study, in a murine model of lung metastatic disease, we explore whether neo-antigen specific T cells are a sensitive marker for the detection of lung cancer after primary tumour resection. We determine lung metastatic disease by histology, and then compare detection by PET-CT and neo-antigen specific T cell frequency. Detection of lung metastatic disease within the histology positive group by PET-CT and neo-antigen specific T cell frequency were 22.9% and 92.2%, respectively. Notably, neo-antigen specific T cells in the lung draining lymph node were indicative of metastatic disease (82.8 ± 12.9 spots/105 cells; mean ± SE), compared to healthy lung control (28.5 ± 8.6 spots/105 cells; mean ± SE). Potentially, monitoring tumour neo-antigen specific T cell profiles is a highly sensitive method for determining disease recurrence.

Second-line systemic therapies for metastatic urothelial carcinoma: a population-based cohort analysis.

Introduction: Patients with urothelial carcinoma (uc) have a poor prognosis after progression on first-line cisplatin-based chemotherapy. Real-world data about second-line cytotoxic therapies are limited. We sought to characterize patients with metastatic uc who receive more than 1 line of systemic therapy and to describe their treatments and outcomes. Methods: Using BC Cancer's pharmacy database, we identified patients with documented metastatic uc who had received more than 1 line of systemic therapy. A retrospective chart review was then performed to collect clinicopathologic, treatment, and outcomes data. Results: The 51 included patients, of whom 42 were men (82%), had a median age of 65 years (range: 38-81 years). Sites of metastasis included lymph nodes (n = 30), bone (n = 7), lung (n = 9), and peritoneum (n = 2). Second-line chemotherapy regimens included gemcitabine-cisplatin [gc (n = 14)], paclitaxel (n = 24), docetaxel (n = 12), and an oral topoisomerase i inhibitor (n = 1). Median time to progression (ttp) and overall survival (os) were 2.0 and 6.83 months respectively. Compared with patients who received a different agent, patients who had experienced a prior response to first-line gc and who were re-challenged with second-line gc had a better median ttp (11.0 months vs. 6.0 months, p = 0.02) and survived longer (4.0 months vs. 1.0 months, p = 0.02). No differences in os between non-gc regimens were evident. Conclusions: In patients with metastatic uc, overall outcomes remain poor, but compared with patients receiving other agents, the subgroup of patients re-challenged with second-line gc demonstrated improved ttp. Conventional chemotherapy regimens provide only modest benefits in the second-line setting and have largely been replaced with immunotherapy.

Systematic review of aromatase inhibitors in the first-line treatment for hormone sensitive advanced or metastatic breast cancer.

To undertake a systematic review of three first-line treatments (letrozole, anastrozole and exemestane) for hormone sensitive advanced or metastatic breast cancer (MBC) in post-menopausal women. We searched six databases from inception up to January 2009 for relevant trials regardless of language or publication status. Randomised controlled clinical trials assessing the safety and efficacy of first-line AIs for post-menopausal women with hormone receptor-positive (HR+, i.e. ER+ and/or PgR+) with or without ErbB2 (HER2)-positive MBC, who have not received prior therapy for advanced or metastatic disease were included. Where meta-analysis using direct or indirect comparisons was considered unsuitable for some or all of the data, we employed a narrative synthesis method. Four studies (25 papers) met the inclusion criteria. From the available evidence, it was possible to directly compare the three AIs with tamoxifen. In addition, by using a network meta-analysis it was possible to compare the three AIs with each other. Based on direct evidence, letrozole seemed to be significantly better than tamoxifen in terms of time-to-progression (TTP) (HR = 0.70 (95% CI: 0.60, 0.82)), objective response rate (RR = 0.65 (95% CI: 0.52, 0.82)) and quality-adjusted time without symptoms or toxicity (Q-Twist difference = 1.5; P < 0.001). Exemestane seemed significantly superior to tamoxifen in terms of objective response rate (RR = 0.68 (95% CI: 0.53, 0.89)). Anastrozole seemed significantly superior to tamoxifen in terms of TTP in one trial (HR = 1.42 (95% CI: 1.15, NR)), but not in the other (HR = 1.01 (95% CI: 0.87, NR)). In terms of adverse events, no significant differences were found between letrozole and tamoxifen. Tamoxifen was associated with significantly more serious adverse events in comparison with exemestane (OR = 0.61 (95% CI: 0.38, 0.97)); while exemestane was associated with significantly more arthralgia in comparison with tamoxifen (OR = 2.33 (95% CI: 1.07, 5.11)). Anastrozole was associated with significantly more total adverse events (OR = 1.04 (95% CI: 1.00, 1.09)) and hot flushes (OR = 1.39 (95% CI: 1.03, 1.89)) in comparison with tamoxifen in one trial; however, the other trial showed no significant differences in adverse events between anastrozole and tamoxifen. The indirect comparison of AIs with each other in women with post-menopausal, hormone sensitive advanced or MBC showed that letrozole and exemestane were better in terms of objective response rate than anastrozole; while the more clinically relevant outcomes overall survival (OS) and progression-free survival (PFS) showed no significant differences between AIs. OS and PFS showed no significant differences between AIs and hence based on these results a class effect for all AIs is possible. However, these results are based on indirect comparisons and a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with appropriate caution. Head-to-head comparisons between letrozole, anastrozole and exemestane in the first-line MBC setting are warranted.

Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling.

OBJECTIVES: To identify combinations of tests and treatments to predict and prevent spontaneous preterm birth. DATA SOURCES: Searches were run on the following databases up to September 2005 inclusive: MEDLINE, EMBASE, DARE, the Cochrane Library (CENTRAL and Cochrane Pregnancy and Childbirth Group trials register) and MEDION. We also contacted experts including the Cochrane Pregnancy and Childbirth Group and checked reference lists of review articles and papers that were eligible for inclusion. REVIEW METHODS: Two series of systematic reviews were performed: (1) accuracy of tests for the prediction of spontaneous preterm birth in asymptomatic women in early pregnancy and in women symptomatic with threatened preterm labour in later pregnancy; (2) effectiveness of interventions with potential to reduce cases of spontaneous preterm birth in asymptomatic women in early pregnancy and to reduce spontaneous preterm birth or improve neonatal outcome in women with a viable pregnancy symptomatic of threatened preterm labour. For the health economic evaluation, a model-based analysis incorporated the combined effect of tests and treatments and their cost-effectiveness. RESULTS: Of the 22 tests reviewed for accuracy, the quality of studies and accuracy of tests was generally poor. Only a few tests had LR+ > 5. In asymptomatic women these were ultrasonographic cervical length measurement and cervicovaginal prolactin and fetal fibronectin screening for predicting spontaneous preterm birth before 34 weeks. In this group, tests with LR- < 0.2 were detection of uterine contraction by home uterine monitoring and amniotic fluid C-reactive protein (CRP) measurement. In symptomatic women with threatened preterm labour, tests with LR+ > 5 were absence of fetal breathing movements, cervical length and funnelling, amniotic fluid interleukin-6 (IL-6), serum CRP for predicting birth within 2-7 days of testing, and matrix metalloprotease-9, amniotic fluid IL-6, cervicovaginal fetal fibronectin and cervicovaginal human chorionic gonadotrophin (hCG) for predicting birth before 34 or 37 weeks. In this group, tests with LR- < 0.2 included measurement of cervicovaginal IL-8, cervicovaginal hCG, cervical length measurement, absence of fetal breathing movement, amniotic fluid IL-6 and serum CRP, for predicting birth within 2-7 days of testing, and cervicovaginal fetal fibronectin and amniotic fluid IL-6 for predicting birth before 34 or 37 weeks. The overall quality of the trials included in the 40 interventional topics reviewed for effectiveness was also poor. Antibiotic treatment was generally not beneficial but when used to treat bacterial vaginosis in women with intermediate flora it significantly reduced the incidence of spontaneous preterm birth. Smoking cessation programmes, progesterone, periodontal therapy and fish oil appeared promising as preventative interventions in asymptomatic women. Non-steroidal anti-inflammatory agents were the most effective tocolytic agent for reducing spontaneous preterm birth and prolonging pregnancy in symptomatic women. Antenatal corticosteroids had a beneficial effect on the incidence of respiratory distress syndrome and the risk of intraventricular haemorrhage (28-34 weeks), but the effects of repeat courses were unclear. For asymptomatic women, costs ranged from 1.08 pounds for vitamin C to 1219 pounds for cervical cerclage, whereas costs for symptomatic women were more significant and varied little, ranging from 1645 pounds for nitric oxide donors to 2555 pounds for terbutaline; this was because the cost of hospitalisation was included. The best estimate of additional average cost associated with a case of spontaneous preterm birth was approximately 15,688 pounds for up to 34 weeks and 12,104 pounds for up to 37 weeks. Among symptomatic women there was insufficient evidence to draw firm conclusions for preventing birth at 34 weeks. Hydration given to women testing positive for amniotic fluid IL-6 was the most cost-effective test-treatment combination. Indomethacin given to all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among symptomatic women. For a symptomatic woman, the most cost-effective test-treatment combination for postponing delivery by at least 48 h was the cervical length (15 mm) measurement test with treatment with indomethacin for all those testing positive. This combination was also the most cost-effective option for postponing delivery by at least 7 days. Antibiotic treatment for asymptomatic bacteriuria of all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among asymptomatic women but this does not take into account the potential side effects of antibiotics or issues such as increased resistance. CONCLUSIONS: For primary prevention, an effective, affordable and safe intervention applied to all mothers without preceding testing is likely to be the most cost-effective approach in asymptomatic women in early pregnancy. For secondary prevention among women at risk of preterm labour in later pregnancy, a management strategy based on the results of testing is likely to be more cost-effective. Implementation of a treat-all strategy with simple interventions, such as fish oils, would be premature for asymptomatic women. Universal provision of high-quality ultrasound machines in labour wards is more strongly indicated for predicting spontaneous preterm birth among symptomatic women than direct management, although staffing issues and the feasibility and acceptability to mothers and health providers of such strategies need to be explored. Further research should include investigations of low-cost and effective tests and treatments to reduce and delay spontaneous preterm birth and reduce the risk of perinatal mortality arising from preterm birth.

Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies.

BACKGROUND: The aetiology of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is still unknown. The identification of risk factors for CFS/ME is of great importance to practitioners. METHOD: A systematic scoping review was conducted to locate studies that analysed risk factors for CFS/ME using multiple predictors. We searched for published and unpublished literature in 11 electronic databases, reference lists of retrieved articles and guideline stakeholder submissions in conjunction with the development of a forthcoming national UK guideline. Risk factors and findings were extracted in a concise tabular overview and studies synthesized narratively. RESULTS: Eleven studies were identified that met inclusion criteria: two case-control studies, four cohort studies, three studies combining a cohort with a case-control study design, one case-control and twin study and one cross-sectional survey. The studies looked at a variety of demographic, medical, psychological, social and environmental factors to predict the development of CFS/ME. The existing body of evidence is characterized by factors that were analysed in several studies but without replication of a significant association in more than two studies, and by studies demonstrating significant associations of specific factors that were not assessed in other studies. None of the identified factors appear suitable for the timely identification of patients at risk of developing CFS/ME within clinical practice. CONCLUSIONS: Various potential risk factors for the development of CFS/ME have been assessed but definitive evidence that appears meaningful for clinicians is lacking.

A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise the seizure focus in people with refractory epilepsy being considered for surgery.

OBJECTIVE: To review the effectiveness and/or accuracy, cost-effectiveness, and predictive value of neuroimaging of the cerebral cortex to visualise the seizure focus in people with refractory epilepsy being considered for surgery. DATA SOURCES: Electronic databases, Internet searches, hand searching and consultation with experts. METHODS: A systematic review was undertaken according to published guidelines. Results of diagnostic accuracy studies were analysed according to the imaging test evaluated. For each study the proportion of patients who were correctly localised, not localised, partially localised or incorrectly localised by the index test was calculated. Due to the heterogeneity present between studies, statistical pooling was not performed. Instead, a narrative synthesis of results is presented. For studies using multivariate analysis to look at the association of neuroimaging findings and outcome following surgery, all factors considered in the analyses were presented. Studies were grouped according to the neuroimaging technique investigated and the findings discussed with reference to possible sources of heterogeneity between studies. RESULTS: No randomised controlled trials (RCTs) were identified, with the majority of studies evaluating the diagnostic accuracy of various imaging techniques in the localisation of epileptic seizure foci. There was significant heterogeneity (p<0.05) between studies for at least one of the localisation categories (correctly localised, not localised, partially localised and incorrectly localised) for all imaging techniques. Possible explanations for this heterogeneity include differing study designs, index test characteristics, reference standards and population characteristics. Test performance was more promising in studies restricted to patients with temporal lobe epilepsy. Ictal single photon emission computed tomography (SPECT) generally had more correctly localising (70--100%) and fewer non-localising (0--7%) scans than other techniques evaluated in patients with temporal lobe epilepsy. Results for computed tomography and interictal SPECT suggest that these tests are relatively poor at localising the seizure focus. Volumeric magnetic resonance imaging (MRI) and position emission tomography (PET) appear promising, and subtraction ictal single photon emission computed tomography co-registered to magnetic resonance imaging (SISCOM) and magnetic resonance spectrosopy (MRS) less promising than ictal SPECT, but these technologies have been assessed in fewer studies. T2 relaxometry was reported in only one small study with inconclusive results. Seventeen studies (33 evaluations) provided sufficient data on the association of a localised scan with outcome following surgery to calculate a relative risk. The majority of evaluations (24/33) suggested that patients with a correctly or partially localised scan had a better outcome following surgery than those with an incorrectly localised or non-localised scan. However, this association was statistically significant in only three studies, two evaluating routine MRI [(relative risk (RR) 2.74, 95% confidence interval (CI): 1.32 to 5.67; RR 1.28, 95% CI: 1.00 to 1.63] and the other SISCOM (RR 2.12, 95% CI: 1.01, 4.44). Nine studies used multivariate analysis to investigate the association of MRI (7 studies), MRS and volumetric MRI (1 study), PET (3 studies), SPECT (1 study) and SISCOM (3 studies) with the outcome following surgery. There was a trend for localisation of abnormalities to be associated with a beneficial outcome. CONCLUSIONS: Due to the limitations of the included studies, the results of this review do little to inform clinical practice, with insufficient evidence regarding effectiveness and cost-effectiveness of imaging techniques in the work-up for epilepsy surgery. Given the inadequacy of existing data, there is a pressing need for studies investigating the utility of imaging techniques in the work up for epilepsy surgery. The most reliable method to achieve this is the RCT, which could examine the single tests or combinations of tests on patient outcome. The authors suggest that it is important that clinicians, patient groups, policy makers and healthcare/research funders meet and debate the most appropriate way to investigate these technologies.

Stool viruses among paediatric patients from a Nairobi clinic, Kenya.

OBJECTIVE: To document the clinical presentation and prevalence of stool viruses among children presenting with symptoms of acute gastroenteritis (AGE) at Gertrude's Garden Children's Hospital, Nairobi, Kenya. DESIGN: Retrospective case-control study. SETTING: A private paediatric clinic in Nairobi. RESULTS: Viral antigen was detectable in the stool samples of 21 (rotavirus alone in ten cases, adenovirus alone in seven cases, and both viruses in four cases). Diarrhoea was almost universally present (20/21 cases) and was reported more frequently than in a control group of ten children with clinical acute gastroenteritis whose stools tested negative for viruses. Fever, an elevated total leukocyte count, and neutrophilia were commonly observed in patients with viral gastroenteritis. Eight children with viral AGE were treated with antibiotics and eight children were admitted to hospital. CONCLUSION: A viral etiology can frequently be identified among children in Nairobi with AGE. Fever, an elevated leukocyte count, and neutrophilia were not helpful in differentiating viral from non-viral AGE in this series. Supportive management consisting of outpatient oral rehydration therapy without antibiotic treatment should be considered in the non-toxic child with AGE.

Interventions targeted at women to encourage the uptake of cervical screening.

BACKGROUND: Cervical cancer is the third most common cancer world-wide. Increasing the uptake of screening, alongside increasing informed choice is of great importance in controlling this disease through prevention and early detection. OBJECTIVES: To assess the effectiveness of interventions aimed at increasing uptake, and informed uptake of cervical cancer screening. SEARCH STRATEGY: Twenty-three electronic databases (to March 2000) were searched with no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs), or quasi-RCTs of interventions to increase uptake/informed uptake of cervical cancer screening. DATA COLLECTION AND ANALYSIS: Data on study characteristics and quality were extracted independently by two reviewers. Where data were available, relative risks and 95% CI were calculated and a chi-squared test for heterogeneity was performed. MAIN RESULTS: Thirty-five studies were included (27 RCTs and eight quasi-RCTs). Heterogeneity between studies limited statistical pooling of data. Overall, however, invitations appear to be effective methods of increasing uptake. In addition, there is limited evidence to support the use of educational materials. The number and quality of included studies limited evidence regarding effectiveness of other interventions. Informed uptake of cervical screening was not considered by any studies. REVIEWER'S CONCLUSIONS: There was some evidence to support the use of invitation letters to increase the uptake of cervical screening. There was limited evidence to support educational interventions but it was unclear what format was most effective. The majority of the studies were from developed countries and so the relevance to developing countries is unclear.

A rapid and systematic review of the clinical effectiveness and cost-effectiveness of topotecan for ovarian cancer.

BACKGROUND: Ovarian cancer is the most common gynaecological cancer with an annual incidence of 21.6 per 100,000 in England and Wales. Due to the often asymptomatic nature of the early stages of the disease, most cases are not detected until the advanced stages. Consequently, the prognosis after diagnosis is poor and the 5-year survival rate in the UK is only about 30%. Current recommendations suggest that first-line chemotherapy for ovarian cancer should involve paclitaxel and platinum (Pt)-based therapy (cisplatin/ carboplatin), however, most patients develop resistant or refractory disease and require second-line therapy. Patients may respond to re-challenge with Pt-agents if the treatment-free interval is > 6 months, but an alternative is often required. Topotecan is one of six drugs currently licensed in the UK for second-line therapy, and recent reviews suggest that it has modest efficacy in the treatment of advanced disease and performs favourably against paclitaxel. However, these reviews are based on a limited number of reports mainly consisting of non-randomised Phase I and II studies. OBJECTIVES OF THE REVIEW: To examine the clinical effectiveness and cost-effectiveness of oral and intravenous topotecan (Hycamtin, SmithKline Beecham, UK) for the treatment of all stages of ovarian cancer. SEARCH STRATEGY: Sixteen electronic databases from inception to September 2000 and Internet resources were searched, in addition to the bibliographies of retrieved articles and submissions from pharmaceutical companies. INCLUSION AND EXCLUSION CRITERIA: Two reviewers independently screened all titles/abstracts and included/excluded studies based on full copies of manuscripts. Any disagreements were resolved through discussion. Only randomised controlled trials (RCTs) and full economic evaluations comparing topotecan to non-topotecan regimens were included. All stages of therapy and disease were considered, and the outcomes included were survival, response, symptom relief, quality of life, adverse effects and costs. METHODS: DATA EXTRACTION STRATEGY: Data were extracted into an Access database by one reviewer and checked by a second. Any disagreements were resolved through discussion. METHODS: QUALITY ASSESSMENT STRATEGY: Two reviewers, using specified criteria, independently assessed the quality of the clinical effectiveness studies and the economic evaluations. Any disagreements were resolved through discussion. METHODS: ANALYSIS STRATEGY: Due to the limited number of studies included in the review and the fact that they compared topotecan with different comparators, the out-come data could not be pooled statistically. Clinical effectiveness data are discussed separately under the different outcome subheadings. For time-to-event data, hazard ratios with 95% confidence intervals are presented where available, and for the remaining outcomes, relative risks are reported or calculated where sufficient data were available. Relative risk data are also presented in the form of Forest plots without pooled estimates. Economic data are presented in the form of a summary and critique of the evidence, and a grading (A-I) assigned to each study indicating the direction and magnitude of the cost-effectiveness data. INCLUDED STUDIES: A total of 568 titles/abstracts were identified and screened for relevance. Full copies of 72 papers were assessed and seven published manuscripts reporting details of two studies of clinical effectiveness and one economic evaluation were included. Further details of the two clinical effectiveness studies and two new economic evaluations were identified from confidential company submissions. Overall, two international multicentre RCTs of effectiveness comparing topotecan with paclitaxel (trial 039) and topotecan with caelyx (trial 30-49) were included in the review. The three economic evaluations included in the review comprised one cost-minimisation analysis (CMA) comparing topotecan with caelyx, one cost-consequences analysis (CCA) comparing topotecan with paclitaxel, etoposide and altretamine and one cost-effectiveness analysis (CEA) comparing topotecan with paclitaxel. RESULTS: QUALITY OF CLINICAL EFFECTIVENESS DATA: Both clinical effectiveness studies (trial 30-49 and 039) were of reasonable quality, although it was unclear whether either performed valid intention-to-treat analyses. In addition, trial 30-49 failed to state whether the outcome assessors were blinded to treatment allocation. RESULTS --QUALITY OF ECONOMIC EVALUATIONS: The CCA (comparing topotecan with three comparators) was of poor quality and of little relevance to the UK NHS. The CMA and CEA were of reasonable quality overall and relevant to the UK NHS. However, both, in particular the CEA, suffered from methodological problems, and thus their findings should be interpreted with caution. RESULTS: ASSESSMENT OF CLINICAL EFFECTIVENESS: The assessment of clinical effectiveness was based on limited data. Only two trials with a total of 709 participants were identified. In general, with a few minor exceptions, there were no statistically significant differences between topotecan and paclitaxel, or topotecan and caelyx in survival, response rate, median time to response, median duration of response and quality of life. Significant differences that were reported were mainly identified in subgroup analyses (Pt-sensitive disease and disease without ascites) of questionable validity and their relevance to a general advanced ovarian cancer patient population undergoing second-line chemotherapy is unclear. However, statistically significant differences were observed in the incidence of adverse effects. Topotecan was associated with increased incidences of haematological toxicities (including neutropenia, leukopenia, anaemia and thrombocytopenia), alopecia, nausea and vomiting. Caelyx-treated patients suffered from significantly increased incidences of Palmar-Plantar erythrodysesthesia, stomatitis, mucous membrane disorders and skin rashes. Paclitaxel was associated with significant increases in alopecia, arthralgia, myalgia, neuropathy, paraesthesiae, skeletal pain and flushing. RESULTS: ASSESSMENT OF COST-EFFECTIVENESS: The assessment of cost-effectiveness was also based on limited data, with three evaluations identified, one of which was not relevant. The two remaining studies, comparing topotecan with paclitaxel (CEA) and topotecan with caelyx (CMA), both used effectiveness data from multicentre RCTs and based their costs on 1999/2000 UK sources. The evaluations were conducted from a UK NHS perspective and findings presented in GB pounds/Euros. Topotecan for the second-line treatment of advanced ovarian cancer was shown to be more cost-effective than paclitaxel (32,513 GB pounds versus 46,186 GB pounds per person in terms of any response (complete or partial), incremental cost-effectiveness = 3065 GB pounds) in all respects except cost per time without toxicity or symptoms, but less cost-effective than caelyx (14,023 GB pounds versus 9979 GB pounds per person regardless of whether the patient responded). However, direct comparisons of the cost findings between the two studies is difficult because they used different designs, different time horizons for the cost analyses and the findings were presented as costs per person for only patients who responded in one study (topotecan versus paclitaxel) and costs per person regardless of whether they responded in the other study (topotecan versus caelyx). CONCLUSIONS: This review indicates that there is little evidence in the form of RCTs on which to base an assessment of the effectiveness of topotecan as second-line therapy for advanced ovarian cancer. The evidence suggests there were no statistically significant differences overall between topotecan and paclitaxel, or topotecan and caelyx in clinical outcomes. However, statistically significant differences were observed in the incidence of adverse effects. The clinical significance of the findings is not discussed. Overall, the effects of topotecan could at best be described as modest, but the alternative agents offer no real advantages except fewer side-effects and possibly improved cost-effectiveness. Both of the clinical effectiveness studies on which this evidence is based had methodological flaws, the most serious being the lack of a blinded assessor in the topotecan versus caelyx trial, which is important for unbiased assessment of response outcomes. The economic evaluations also suffered from a number of potential problems. CONCLUSIONS: RECOMMENDATIONS FOR RESEARCH: Further good quality RCTs and CEAs are required comparing topotecan with other licensed and potentially useful (soon to be licensed) second-line treatments for ovarian cancer. At present, it is difficult to make any decisions about topotecan and other drugs for second-line therapy without good quality direct comparisons. In view of the ongoing studies identified, an update of the current review should be considered in approximately 18 months (Summer 2002) or possibly sooner if the recently commissioned National Institute for Clinical Excellence review of caelyx for ovarian cancer identifies additional data relevant to topotecan.

The Scottish Heart and Arterial Risk Prevention (SHARP) survey of cardiovascular risk: regional differences.

The objective was to explore variation in cardiovascular risk profiles within the Scottish workforce over different regions of Scotland by a planned review of survey data of workplaces throughout Scotland, surveyed between December 1991 and March 1996. The subjects sampled were 19,400 men and women aged between 18 and 70, who were in work and apparently healthy at the time of screening. The results showed that the regions of Scotland may be distinguished through particular risk factors and also by using a single summary score (the SHARP risk score). Overall the Perth and Kinross region tops the league for cardiovascular risk (with the main contributing factors being smoking and high blood pressure); regions of least risk are Inverness-shire and Edinburgh. There are statistically significant differences to be discerned in the regional distribution of cardiovascular risk within the working population of Scotland.

Increasing informed uptake and non-uptake of screening: evidence from a systematic review.

OBJECTIVE: To report data relating to the informed uptake of screening tests. SEARCH STRATEGY: Electronic databases, bibliographies and experts were used to identify relevant published and unpublished studies up until August 2000. INCLUSION CRITERIA: RCTs, quasi-RCTs and controlled trials of interventions aimed at increasing the informed uptake of screening. All participants were eligible as defined by the entry criteria of individual programmes. Studies had to report actual uptake and meet three out of four criteria used to define informed uptake. DATA EXTRACTION AND SYNTHESIS: Relevant studies were identified, data extracted and their validity assessed by two reviewers independently. Outcome data included screening uptake, knowledge, informed decision-making and attitudes to screening. A random-effects model was used to calculate individual relative risks and 95% confidence intervals. MAIN RESULTS: Six controlled trials (five RCTs and one quasi-RCT), focusing on antenatal and prostate specific antigen screening, were included. All reported risks/benefits of screening and assessed knowledge. Two also assessed decision-making. Two reported risks/benefits to all randomized groups and evaluated different ways of presenting information. Neither found that interventions such as videos, information leaflets with decision trees, or touch screen computers conveyed any additional benefits over well-prepared leaflets. CONCLUSIONS: There is some evidence to suggest that changing the format of informed choice interventions in screening does not alter knowledge, satisfaction or decisions about screening. It is not clear whether informed choice in screening affects uptake. More well-designed RCTs are required and further research should also be directed towards the development of a valid instrument for measuring all components of informed choice in screening.