Complication rate among people with diabetes at low risk of foot ulceration in Fife, UK: an analysis of routinely collected data.

AIMS: To estimate the rate at which people with diabetes and a low risk of foot ulceration change diabetic foot ulceration risk status over time, and to estimate the rate of ulceration, amputation and death among this population. METHODS: We conducted an observational study of 10 421 people with diabetes attending foot screening in an outpatient setting in NHS Fife, UK, using routinely collected data from a national diabetes register, NHS SCI Diabetes. We estimated the proportion of people who changed risk status and the cumulative incidence of ulceration, amputation and death, respectively, among people with diabetes at low risk of diabetic foot ulceration at 2-year follow-up. RESULTS: At 2-year follow-up, 5.1% (95% CI 4.7, 5.6) of people with diabetes classified as low risk at their first visit had progressed to moderate risk. The cumulative incidence of ulceration, amputation and death was 0.4% (95% CI 0.3, 0.6), 0.1% (95% CI 0.1, 0.2) and 3.4% (95% CI 3.1, 3.8), respectively. CONCLUSIONS: At 2-year follow-up, 5% of people at low risk of diabetic foot ulceration changed clinical risk status and <1% of people experienced foot ulceration or amputation. These findings provide information which will help to inform the current debate regarding optimal foot screening intervals.

Expression of the novel Wnt receptor ROR2 is increased in breast cancer and may regulate both ß-catenin dependent and independent Wnt signalling.

PURPOSE: Wnt signalling has been implicated in breast cancer, and in particular aberrant ß-catenin-independent Wnt signalling has been associated with breast cancer metastasis and Tamoxifen resistance. Despite Wnt pathway involvement in many human cancers, attempts to target the pathway therapeutically have been disappointing. The recent discovery that the receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a novel Wnt receptor provides a potential new therapeutic and diagnostic target. METHODS: To clarify the role of ROR2 in breast cancer, we investigated its expression via ROR2 immunohistochemistry in a clinical cohort of breast cancer patients, and via in vitro studies incorporating both overexpression and knock-down of ROR2. RESULTS: ROR2 was expressed in the majority of breast cancer patients (87%), including those classed as triple negative. Breast cancer patients expressing ROR2 had a significantly shorter overall survival than those lacking ROR2 expression (P < 0.05). Overexpression of ROR2 in the mammary epithelial cell line, MCF10A, increased both ß-catenin-dependent and ß-catenin-independent targets and decreased cell adhesion. Knock-down of ROR2 in the breast cancer cell lines, MDA-MB-453 and HCC1143, decreased both ß-catenin-dependent and ß-catenin-independent targets and increased cell adhesion. Treatment of ROR2-expressing breast cancer cells with the novel berberine derivative, NAX53, significantly inhibited cell proliferation and migration. CONCLUSIONS: This is the first study to report the expression of ROR2 in breast cancer. Breast cancer patients expressing ROR2 had a significantly worse prognosis than those lacking ROR2. ROR2 may regulate both ß-catenin-dependent and ß-catenin-independent Wnt signalling pathways, and represents a potential diagnostic and therapeutic target.

Comparative efficacy of tyrosine kinase inhibitor treatments in the third-line setting, for chronic-phase chronic myelogenous leukemia after failure of second-generation tyrosine kinase inhibitors.

We compared the efficacy of ponatinib and second-generation tyrosine kinase inhibitors (2G-TKIs: bosutinib, dasatinib, and nilotinib) in chronic phase CML resistant/intolerant to ≥1 prior 2G-TKI. Estimated probabilities of CCyR with 2G-TKI ranged from 22% to 26%, compared with 60% (95% CrI 52-68%) with ponatinib. The estimated probability of ponatinib providing higher response rate than all other included treatments was 99% (CCyR) and 97% (MCyR). Use of further 2G-TKI may provide limited benefit in CP-CML patients resistant/intolerant to prior 2G-TKI treatment. Compared with 2G-TKIs, ponatinib is estimated to provide substantially higher probability of achieving CCyR and MCyR; safety was not compared.

RAD21 cohesin overexpression is a prognostic and predictive marker exacerbating poor prognosis in KRAS mutant colorectal carcinomas.

BACKGROUND: RAD21 is a component of the cohesion complex and is integral to chromosome segregation and error-free DNA repair. RAD21 is functionally important in tumour progression but its role in colorectal carcinoma (CRC) is unclear. We therefore assessed its clinicopathological and prognostic significance in CRC, as well as its effect on chemosensitivity. METHODS: A retrospective observation study examined RAD21 expression in 652 CRCs using a tissue microarray approach. Correlation with clinicopathological factors including gender, tumour grade, mucinous subtype, TNM stage, disease-specific survival (DSS), BRAF and KRAS mutation status, tumour p53 immunostaining, tumour microsatellite instability and tumour CpG island methylator phenotype was performed. Colorectal cancer cell clones with stable RAD21 knockdown were generated and tested for cellular sensitivity to conventional chemotherapeutic drugs. RESULTS: RAD21 expression was significantly correlated with male gender (56.7% vs 43.3%, P=0.02), well-differentiated histology (14.4% vs 4.0%, P=0.0001), higher T-stage (36.1% vs 27.0%, P=0.01), presence of metastasis (18.8% vs 12.6%, P=0.03), and shorter DSS (hazard ratio (HR) 1.4, 95% CI 1.1 to 1.9, P=0.01) in both univariate and multivariate analysis. RAD21 expression was associated with shorter DSS in patients with KRAS mutant tumours (HR:2.6, 95% CI:1.4-4.3, P=0.001) and in patients receiving adjuvant chemoradiotherapy (HR:1.9, 95% CI:1.2-3.0, P=0.008). Colorectal cancer cells with RAD21 knockdown exhibited enhanced sensitivity to 5-fluorouracil, either alone or in combination with oxaliplatin. CONCLUSIONS: RAD21 expression in CRC is associated with aggressive disease especially in KRAS mutant tumours and resistance to chemoradiotherapy. RAD21 may be an important novel therapeutic target.

Primary care provider practices and beliefs related to cervical cancer screening with the HPV test in Federally Qualified Health Centers.

OBJECTIVE: Cervical cancer screening using the human papillomavirus (HPV) test and Pap test together (co-testing) is an option for average-risk women ≥ 30 years of age. With normal co-test results, screening intervals can be extended. The study objective is to assess primary care provider practices, beliefs, facilitators and barriers to using the co-test and extending screening intervals among low-income women. METHOD: Data were collected from 98 providers in 15 Federally Qualified Health Center (FQHC) clinics in Illinois between August 2009 and March 2010 using a cross-sectional survey. RESULTS: 39% of providers reported using the co-test, and 25% would recommend a three-year screening interval for women with normal co-test results. Providers perceived greater encouragement for co-testing than for extending screening intervals with a normal co-test result. Barriers to extending screening intervals included concerns about patients not returning annually for other screening tests (77%), patient concerns about missing cancer (62%), and liability (52%). CONCLUSION: Among FQHC providers in Illinois, few administered the co-test for screening and recommended appropriate intervals, possibly due to concerns over loss to follow-up and liability. Education regarding harms of too-frequent screening and false positives may be necessary to balance barriers to extending screening intervals.

Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/ß-catenin signalling thresholds for tumourigenesis.

Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/ß-catenin signalling levels 'just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282-1581) leaving 1-3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5' to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2-3 intact 20AARs were associated with 5' mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3' to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2-3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate 'fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/ß-catenin signalling, with different 'optimal' thresholds for proximal and distal cancers.

Efficacy of biologics in the treatment of moderate to severe psoriasis: a network meta-analysis of randomized controlled trials.

BACKGROUND: Ustekinumab, a novel monoclonal antibody for the treatment of moderate to severe plaque-type psoriasis, has recently received regulatory approval in Europe, bringing the total number of biologic agents licensed in this indication to five. To assist treatment selection in daily practice it is essential to understand the benefit/risk profile of these agents and in the absence of a clinical trial comparing all available biologics a number of reviews have used statistical techniques to generate estimates of the comparative effectiveness of these therapies through the available network of randomized clinical trials. These estimates have previously been published for a limited range of psoriasis biologic treatments, although, to date no review has compared all the currently available agents in Europe. OBJECTIVES: To estimate the comparative effectiveness of all biologic agents indicated in the treatment of moderate to severe psoriasis currently available in Europe based on the primary trial endpoints. METHODS: A number of databases were searched for details of randomized controlled trials of available biologics in the treatment of plaque-type psoriasis in adults. Comparative effectiveness was estimated based on the reported Psoriasis Area and Severity Index (PASI) 50, 75 and 90 response rates. A network meta-analysis conducted on the ordered probit scale and implemented as a Bayesian hierarchical model provided estimates for the probability of response and relative risk vs. placebo, based on all observed comparisons. RESULTS: Twenty trials were included in the meta-analysis including patients with a mean disease duration of 18-22years. Based on the indirect comparison and given a placebo PASI 50 response of 13%, infliximab had the highest predicted mean probability of response at PASI levels 50 (93%), 75 (80%) and 90 (54%), followed by ustekinumab 90 mg at 90%, 74% and 46%, respectively, and then ustekinumab 45mg, adalimumab, etanercept and efalizumab. CONCLUSIONS: The ordered probit model allowed a quantitative comparison of all currently licensed biologics, providing estimates on comparative effectiveness and a suggested ranking of treatments that is of potential use to decision-makers. However, the analysis is based on indirect comparisons of the primary endpoint reported from short-term randomized trials.

Transfusion practice in major obstetric haemorrhage: lessons from trauma.

The management of massive haemorrhage with blood products is changing as evidence arrives from civilian and military trauma. Rapid early replacement of coagulation factors and platelets is now becoming central to improving outcome, usually given in higher ratios with respect to red cell units than previously recommended and using empiric transfusion based on clinical rather than laboratory parameters. The management of three cases of major obstetric haemorrhage based on these principles is presented. Packed red blood cells, fresh frozen plasma, platelets and cryoprecipitate were transfused in the ratios 5:2:2:1, 4.5:1:1:1 and 4.5:2:1:1. Each patient had acceptable full blood count and coagulation results after surgery and all made an uneventful recovery. These outcomes support the opinion that major obstetric haemorrhage can be managed in a similar fashion to blood loss in trauma. Recommendations from the Association of Anaesthetists of Great Britain and Ireland, and the UK National Patient Safety Agency should be considered during major obstetric haemorrhage.

Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma.

AIMS: To determine the prevalence of colorectal polyps of different types in an unselected population, and to correlate the morphological diagnoses with BRAF mutation analysis. METHODS: Cases of colorectal polyps diagnosed at endoscopy were retrieved from the files of Southern.IML Pathology. All slides were reviewed and the lesions classified histologically. A diagnosis of sessile serrated adenoma was made even if the characteristic features were present only focally. If there was more than one polyp of a particular type in any patient, one lesion was chosen at random so that the results represent the number of patients with each type of polyp rather than the total number of polyps. A proportion of the polyps was subjected to BRAF mutation analysis. RESULTS: A total of 1479 patients were identified. Non-serrated ("conventional") adenomas were found in 964 patients (65%), hyperplastic polyps in 437 (30%), sessile serrated adenomas in 57 (3.9%), traditional serrated adenomas in 11 (0.7%) and mixed hyperplastic adenomatous polyps in 10 (0.7%). BRAF V600E mutation analysis was performed in 148 selected cases; mutations were found in 44/49 (90%) of lesions diagnosed as sessile serrated adenoma, in 10/34 (29%) of hyperplastic polyps of microvesicular type, in 4/11 (36%) of traditional serrated adenomas, in 10/10 (100%) of mixed hyperplastic adenomatous polyps, and in 2/42 (5%) of "conventional" adenomas. CONCLUSIONS: Sessile serrated adenomas are encountered commonly in routine endoscopy practice. The histological diagnosis correlates strongly with the presence of BRAF mutation.

A systematic review and economic model of switching from non-glycopeptide to glycopeptide antibiotic prophylaxis for surgery.

OBJECTIVES: To determine whether there is a level of methicillin-resistant Staphylococcus aureus (MRSA) prevalence at which a switch from non-glycopeptide to glycopeptide antibiotics for routine prophylaxis is indicated in surgical environments with a high risk of MRSA infection. DATA SOURCES: Major electronic databases were searched up to September 2005. REVIEW METHODS: The effectiveness review included controlled clinical trials comparing a glycopeptide with an alternative antibiotic regimen that reported effectiveness and/or adverse events. Controlled observational studies were also included for adverse events. The cost-effectiveness review included economic evaluations comparing glycopeptide prophylaxis with any alternative comparator. Study validity was assessed using standard checklists. The supplementary economic reviews assessed evaluations of non-glycopeptide antibiotic prophylaxis; evaluations where antibiotic resistance is a problem; methods of modelling resistance in infectious diseases; and developing a conceptual framework. An indicative decision analytic model was developed to compare vancomycin with a cephalosporin and with a combination of vancomycin and cephalosporin, using hip arthroplasty as an exemplar. Available data on, for example, surgical site infection (SSI) rates, MRSA rates, effectiveness of the antibiotics, were incorporated into the model. Costs were estimated from the perspective of the NHS. RESULTS: The effectiveness review included 16 randomised controlled trials, with a further three studies included for adverse events only. There was no evidence that glycopeptides were more effective than non-glycopeptides in preventing SSIs. Most of the trials did not report either the baseline prevalence of MRSA at the participating surgical units or MRSA infections as an outcome. The cost-effectiveness review included five economic evaluations of glycopeptide prophylaxis. Only one study incorporated health-related quality of life and undertook a cost-utility analysis. None of the studies was undertaken in the UK and none explicitly modelled antibiotic resistance. The supplementary reviews provided few insights into how to assess cost-effectiveness in the context of resistance. No studies modelled cost-effectiveness alongside epidemiological models of resistance. There was little information regarding the impact of surgical infections on costs post-discharge and patient quality of life. The lack of available clinical evidence limited the development of the cost-effectiveness model and meant that the modelling could only be indicative in nature. The model can be used to show the threshold baseline risk at which the use of vancomycin as prophylaxis might be cost-effective (the model did not include teicoplanin). The indicative model suggests that the baseline risk of MRSA can be fairly modest at below the national average and it would still appear cost-effective to use glycopeptide prophylaxis. The model indicates that the use of glycopeptides as a form of prophylaxis in addition to a treatment for MRSA infections is unlikely to decrease the total usage and hence reduce the risk of future problems with glycopeptide-resistant bacteria. CONCLUSIONS: There is insufficient evidence to determine whether there is a threshold prevalence of MRSA at which switching from non-glycopeptide to glycopeptide antibiotic prophylaxis might be clinically effective and cost-effective. Future research needs to address the complexities of decision-making relating to the prevention of MRSA and infection control in general. Research including evidence synthesis and decision modelling comparing a full range of interventions for infection control, which extends to other infections, not just MRSA, is needed. A long-term research programme to predict the pattern of drug resistance and its implications for future costs and health is also needed.

The cost-effectiveness of etanercept and infliximab for the treatment of patients with psoriatic arthritis.

OBJECTIVE: Tumour necrosis factor (TNF) antagonists have been shown to improve the outcomes in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We assess the cost-effectiveness of two TNF antagonists and so-called 'palliative care' for the treatment of active PsA from the perspective of the UK National Health Service (NHS). METHODS: Bayesian statistical methods were used to synthesize evidence from three Phase III trials, identified through a systematic review, and estimate the relative efficacy of etanercept, infliximab and palliative care. A probabilistic decision analytic model was then used to compare these treatments after the failure of at least two conventional disease-modifying anti-rheumatic drugs (DMARDs), following the British Society for Rheumatology (BSR) guidelines for use. The primary outcome measure, quality-adjusted life years (QALYs), was derived from utility values estimated as a function of disability measured by the Health Assessment Questionnaire (HAQ). The deterioration experienced in HAQ at treatment withdrawal (rebound) was incorporated using alternative scenarios to represent best- and worst-case assumptions. The model was extended beyond the trial duration to a 10-yr and lifetime horizon, using available evidence and expert opinion-based assumptions on disease progression. Resource utilization was based on literature, national databases and expert opinion. Prices were obtained from routine NHS sources and published literature. RESULTS: At a 10-yr time horizon, the incremental cost-effectiveness ratio (ICER) for etanercept compared with palliative care was pound sterling26 361 per QALY gained for the best-case rebound scenario, which increased to pound sterling30 628 for the worst-case. The ICERs for infliximab compared with etanercept were pound sterling165 363 and pound sterling205 345 per QALY, respectively. These findings are mainly explained by the fact that infliximab has higher acquisition and administration costs without substantially superior effectiveness compared with etanercept. Results were sensitive to estimates of rebound assumptions at withdrawal and the time horizon. CONCLUSIONS: Only results for etanercept remained within the range of cost-effectiveness estimates considered to represent value for money in the NHS by the National Institute for Health and Clinical Excellence. Further research appears most valuable in relation to the short-term effectiveness, utility parameters and assumptions regarding the effect of rebound.

The collagenase-1 (MMP-1) gene promoter polymorphism - 1607/2G is associated with favourable prognosis in patients with colorectal cancer.

Matrix metalloproteinase (MMP) overexpression has been implicated in the pathogenesis of colorectal carcinoma (CRC). Accumulating evidence suggests that MMP promoter single nucleotide polymorphisms (SNPs) effecting gene transcription are associated with enhanced susceptibility for the development of malignant disease, increased tumour invasiveness and poor patient survival. The aim of the current investigation was to determine whether such associations exist in a large CRC patient/control study population. Using an allelic discrimination real-time polymerase chain reaction, polymorphisms in the MMP-1, MMP-2 and MMP-3 gene promoters (-1607, -1306, and -1612 bp, respectively) were assessed in normal blood mononuclear cells from patients with CRC (n=503) and control subjects (n=471). Genotypes corresponding to each MMP SNP were correlated with tumour characteristics and clinical outcome. The frequency of each genotype was not statistically different between patients and control subjects and no significant differences were noted between the genotypes and tumour characteristics for the three MMP SNPs. CRC patients with the 2G/2G genotype for the MMP-1 SNP had significantly better 5-year survival compared to patients with a 1G allele (P<0.05). Our results demonstrate that CRC patients with a 2G/2G genotype in the MMP-1 gene promoter SNP have a favourable prognosis. Although our results were unexpected, given that this genotype is associated with enhanced MMP-1 transcriptional activity, they are consistent with recent data highlighting the anti-tumorigenic properties of MMPs.

Etanercept and efalizumab for the treatment of psoriasis: a systematic review.

OBJECTIVES: To evaluate the clinical effectiveness, safety, tolerability and cost-effectiveness of etanercept and efalizumab for the treatment of moderate to severe chronic plaque psoriasis. DATA SOURCES: Major electronic databases and several Internet resources were searched up to April 2004. REVIEW METHODS: Systematic reviews were undertaken of the efficacy, safety and economic reviews of etanercept and efalizumab. An existing systematic review of the efficacy and safety of other treatments was also updated. Economic models supplied by the manufacturers of etanercept and efalizumab were critiqued. An economic model was then developed of etanercept and efalizumab in the treatment of moderate to severe chronic plaque psoriasis. RESULTS: The review of the clinical evidence identified a total of 39 published and three unpublished studies: eight randomised controlled trials (RCTs) of the efficacy of etanercept (three trials) and efalizumab (five); 10 studies of the adverse effects of the interventions; and 24 RCTs of the efficacy of the other treatments for moderate to severe psoriasis. The trials of the efficacy of the interventions were all double-blind and placebo-controlled trials and generally of good quality, but three of the five efalizumab trials were poorly reported. A total of 1347 patients were included in the etanercept trials and 2963 in the efalizumab trials. Data on the efficacy of etanercept 25 mg twice a week for 12 weeks were available from three RCTs. On average, active treatment resulted in 62% of patients achieving a Psoriasis Area and Severity Index (PASI) 50, 33% achieving a PASI 75, 11% achieving a PASI 90 and 40% were assessed as clear or almost clear. These figures are not adjusted for changes relative to placebo. Improvement in quality of life as assessed by mean percentage change in Dermatology Life Quality Index (DLQI) was around 59% with etanercept 25 mg twice a week compared with 9% with placebo, and all mean differences that could be calculated were statistically significantly in favour of etanercept. Data on the efficacy of etanercept 50 mg twice a week for 12 weeks were available from two RCTs. Across the two trials, the proportion of patients achieving PASI 50, 75 and 90 was 76, 49 and 21%, respectively; the pooled relative risks were all statistically significantly in favour of etanercept. The findings for mean PASI after treatment, mean percentage change in PASI from baseline and mean percentage change in DLQI also demonstrated the efficacy of etanercept treatment. Evidence from one RCT indicates that the response to etanercept is maintained post-treatment, at least in the medium term, and data from uncontrolled follow-up phases reflect and extend these findings. Efalizumab at a dose of 1 mg/kg once a week subcutaneously was studied in five RCTs. Across these trials, 12 weeks of active treatment resulted in an average of 55% of patients achieving PASI 50, 27% PASI 75, 4.3% PASI 90 and 27% clear or minimal psoriasis status. These figures are not adjusted for changes relative to placebo. There is no evidence from RCTs that the response to efalizumab 1 mg/kg once a week is maintained when treatment continues beyond 12 weeks, and long-term follow-up data relate to a range of doses and are poorly reported and so cannot be used to draw even tentative conclusions regarding the long-term efficacy of efalizumab. Uncontrolled data from trial follow-up suggest that time to relapse may be around 60 days. No data indicating the existence or absence of any rebound in psoriasis after discontinuation of efalizumab were identified. There is no evidence relating to the efficacy of efalizumab upon retreatment. A mixed treatment comparison analysis found a higher response rate in terms of PASI 50, 75 and 90 with etanercept than with efalizumab. Injection site reactions appear to be the most common adverse effects of etanercept. Overall, etanercept appears to be well tolerated in short- and long-term use, although many of the long-term data are not from patients with psoriasis. Headache, chills and, to a lesser extent, nausea, myalgia, pain and fever are the common adverse events associated with efalizumab. Overall, withdrawal rates due to adverse events are low. Longer term data for efalizumab are not readily available for evaluation, but the adverse events data up to 3 years appear to reflect those over 12 weeks and to remain stable. Unfortunately, few data for serious infections and serious adverse events with efalizumab are available. For the primary analysis comparing etanercept, efalizumab and supportive care, the results of the York Model suggest that the biological therapies would only be cost-effective for all patients with moderate to severe psoriasis if the NHS were willing to pay over pound 60,000 per QALY gained. In patients with poor baseline quality of life (fourth quartile DLQI), efalizumab, etanercept 25 mg (intermittent), etanercept 25 mg (continuous) and etanercept 50 mg (intermittent) would be cost-effective as part of a treatment sequence if the NHS were willing to pay pound 45,000, pound 35,000, pound 45,000 and pound 65,000 per QALY gained, respectively. In patients who are also at high risk of inpatient hospitalisation (21 days per annum), these therapies would be cost-effective as part of a sequence as long as the NHS were willingness to pay pound 25,000, pound 20,000, pound 25,000 and pound 45,000 per QALY gained, respectively. As part of a secondary analysis including a wider range of systemic therapies as comparators, the York Model found that it would only be cost-effective to use etanercept and efalizumab in a sequence after methotrexate, ciclosporin and Fumaderm. CONCLUSIONS: Clinical trial data indicate that both etanercept and efalizumab are efficacious in patients who are eligible for systemic therapy, but the economic evaluation demonstrates that these biological therapies are likely to be cost-effective only in patients with poor baseline QoL and who are at risk of hospitalisation. Efficacy trials conducted in the specific population for which etanercept and efalizumab are licensed are required, as are long-term comparisons of etanercept and efalizumab with other treatments for moderate to severe psoriasis. Long-term efficacy trials and safety/tolerability data for patients treated with etanercept or efalizumab are required, as are trials on the response of specific subtypes of psoriasis to different drugs. Research on the rate of inpatient hospitalisation in patients with moderate to severe psoriasis is warranted, and the effect of treatment on this rate.

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer.

Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration.

Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.

OBJECTIVES: To evaluate the clinical effectiveness, safety, tolerability and cost-effectiveness of etanercept and infliximab for the treatment of active and progressive psoriatic arthritis (PsA) in patients who have inadequate response to standard treatment, including disease-modifying antirheumatic drug (DMARD) therapy. DATA SOURCES: Electronic databases were searched up to July 2004. REVIEW METHODS: A systematic review evaluated the clinical efficacy and adverse effects of etanercept and infliximab. The efficacy of DMARDs in the treatment of PsA was also reviewed and treatments were compared using Bayesian evidence synthesis methods. Following evaluation of existing economic evaluations of etanercept and infliximab in PsA, a new economic model was developed (the York Model). This utilised the results from the evidence synthesis and data from a range of other sources. RESULTS: Across the two trials, at 12 weeks, around 65% of patients treated with etanercept achieved an American College of Rheumatology (ACR) 20 {pooled relative risk (RR) 4.19 [95% confidence interval (CI) 2.74 to 6.42]}, demonstrating a basic degree of efficacy in terms of arthritis-related symptoms. In addition, around 45% of patients treated with etanercept achieved an ACR 50 [pooled RR 10.84 (95% CI 4.47 to 26.28)] and around 12% achieved an ACR 70 [pooled RR 16.28 (95% CI 2.20 to 120.54)], demonstrating a good level of efficacy. The subgroup analyses conducted in one trial revealed that the effect of etanercept was not dependent upon patients' concomitant use of methotrexate. In addition, almost 85% of patients treated with etanercept achieved a Psoriatic Arthritis Response Criteria (PsARC) [pooled RR 2.60 (95% CI 1.96 to 3.45). The Psoriatic Area and Severity Index (PASI) results indicate some beneficial effect on psoriasis at 12 weeks; however, the data are sparse. The statistically significant reduction (improvement) in Health Assessment Questionnaire (HAQ) score with etanercept compared with placebo indicates a beneficial effect of etanercept on function. Similar results were seen at 24 weeks, except that the results for PASI 75 and PASI 50 now achieved statistical significance and data for Total Sharp Score annualised rate of progression were available; this was statistically significantly lower in etanercept-treated patients than in placebo-treated patients. Uncontrolled follow-up of patients indicates that treatment benefit may be maintained for at least 50 weeks. At 16 weeks, 65% of patients treated with infliximab achieved an ACR 20 [RR 6.80 (95% CI 2.89 to 16.01)], demonstrating a basic degree of efficacy in terms of arthritis-related symptoms. This level of efficacy was not dependent upon patients' concomitant use of methotrexate. Almost half the patients treated with infliximab achieved an ACR 50 [RR 49.00 (95% CI 3.06 to 785.06)] and over one-quarter achieved an ACR 70 [RR 31.00 (95% CI 1.90 to 504.86)] compared with none of the placebo group, demonstrating a good level of efficacy. In addition, 75% of patients treated with infliximab achieved a PsARC [RR 3.55 (95% CI 2.05 to 6.13)]. The beneficial treatment effect on psoriasis was also statistically significant with a mean difference in percentage change from baseline in PASI of -5 (95% CI -6.8 to -3.3), as was the percentage improvement from baseline in HAQ score with infliximab compared with placebo [mean difference 51.4 (95% CI 48.08 to 54.72)], indicating a beneficial effect of infliximab on functional status. Uncontrolled data from all measures of joint disease, psoriasis and HAQ collected up to 50 weeks of follow-up reflect those at 16 weeks. There were no radiographic assessments, so nothing can be determined about the potential or otherwise of infliximab to delay the progression of joint disease. Using the York cost-effectiveness model, infliximab was consistently dominated by etanercept because of its higher acquisition and administration costs without superior effectiveness. The incremental cost per quality-adjusted life-year (QALY) gained of etanercept compared with palliative care ranged from 14,818 pounds (females, 40-year time horizon) to 49,374 pounds (males, 1-year time horizon) if it is assumed that, when patients eventually fail on biological therapy, their disability (in terms of HAQ score) deteriorates by the same amount as it improved when they initially respond to treatment (rebound equal to gain). Results for etanercept ranged from 25,443 pounds (females, 40-year time horizon) to 49,441 pounds (males, 1-year time horizon) per QALY gained under the assumption that, when patients fail on therapy, their disability level returns to what it would have been had they never responded (rebound equal to natural history). CONCLUSIONS: The limited data available indicated that etanercept and infliximab are efficacious in the treatment of PsA with beneficial effects on both joint and psoriasis symptoms and on functional status. Short-term data indicated that etanercept can delay joint disease progression, but long-term data are needed. There are no controlled data as yet to indicate that infliximab can delay joint disease progression. Treatment with both etanercept and infliximab for 12 weeks demonstrated a significant degree of efficacy, with no statistically significant difference between them. For both drugs, adverse events were common with mild injection/infusion reactions being the main treatment-related effect. The York model indicated that etanercept is more cost-effective than infliximab as it has a lower cost with little difference in outcomes. The cost-effectiveness of etanercept is also sensitive to assumptions made about the extent of disease progression when patients are responding to therapy. The number of years for which a patient can be safely on biologicals is uncertain so these results should be considered with caution. Further research should include long-term controlled trials to confirm benefits, review adverse events and to explore further the implications of biologic therapy.

Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda) for locally advanced and/or metastatic breast cancer.

OBJECTIVE: To examine the clinical effectiveness and cost-effectiveness of oral capecitabine for locally advanced and metastatic breast cancer in relation to its licensed indications. DATA SOURCES: Twenty-three electronic databases and other databases of ongoing research and Internet resources, bibliographies of retrieved articles and industry submissions. REVIEW METHODS: Two reviewers independently screened and assessed all titles and/or abstracts including economic evaluations. Randomised controlled trials (RCTs) and observational studies that investigated capecitabine monotherapy, in patients pretreated with an anthracycline-containing regimen or a taxane, or capecitabine in combination with docetaxel, in patients pretreated with an anthracycline-containing regimen, were included. The economic evaluation was based on data reported in the manufacturer's submission. RESULTS: For capecitabine monotherapy, 12 uncontrolled observational studies were identified. The methodological quality of the studies was low. Capecitabine demonstrated antitumour activity, but was associated with a particular risk of hand-foot syndrome and diarrhoea. Economic evaluation was hampered by the poor quality of the published studies, but compared indirectly with vinorelbine, capecitabine was associated with lower costs and improved patient outcomes. For capecitabine in combination with docetaxel, one RCT was identified. Combination therapy was superior to single-agent docetaxel in terms of survival, time to disease progression and overall response. Adverse events occurred more frequently with combination therapy. The economic evaluation demonstrated an overall improved QALY score for combination therapy with a slight reduction in costs. CONCLUSIONS: No conclusions could be drawn regarding the therapeutic benefit of capecitabine monotherapy; RCTs are required. Capecitabine appeared cost-effective compared with vinorelbine, but serious doubts remain; the poor quality of the trials may invalidate this conclusion. Based on limited evidence, combination therapy was more effective than single-agent docetaxel and likely to be cost-effective, but was associated with higher incidences of hand-foot syndrome, nausea, diarrhoea and stomatitis.

Effect of different nutritional regimens before ovulation on plasma concentrations of metabolic and reproductive hormones and oocyte maturation in gilts.

This study examined the effect of feeding either a maintenance (1.35 kg day(-1)) or high (3.5 kg day(-1)) plane of nutrition for 19 days after oestrus on oocyte maturity and both reproductive and metabolic hormone concentrations in gilts. Blood samples were collected each day from oestrus until slaughter on day 19 and during two pulse bleeds (15 min samples for 8 h) conducted on day 12 and day 18. After slaughter, oocytes were recovered from the presumed ovulatory population of follicles, matured in vitro for 46+/-2 h with 10% of their own follicular fluid, and then fixed and stained to determine the stage of nuclear maturation of the oocyte. Gilts fed the high diet had a higher proportion of oocytes that reached metaphase II than gilts fed the maintenance diet (88.3+/-2.71% versus 68.2+/-6.48%; P=0.013). Circulating concentrations of insulin-like growth hormone I (IGF-I) and the number of LH pulses were lower (P<0.05) in gilts fed the maintenance diet compared with gilts fed the high diet on day 12 and day 18. Mean oestradiol and progesterone concentrations were higher (P<0.05) for gilts fed the maintenance diet compared with gilts fed the high diet. Leptin concentrations were also higher on day 19 in gilts fed the high diet (2.16+/-0.26 ng ml(-1) (n=9) versus 3.20+/-0.32 (n=11), P=0.025). The results of this study indicate that improved oocyte quality (increased proportion of oocytes that reached metaphase II) is associated with a number of changes in reproductive and metabolic hormones. Further studies are required to indicate which hormonal mechanism may, in turn, lead to increased embryo survival and eventual litter size.

CD103+ intraepithelial lymphocytes--a unique population in microsatellite unstable sporadic colorectal cancer.

Colorectal cancers with microsatellite instability (MSI) typically show increased numbers of intraepithelial lymphocytes (IEL) in comparison to microsatellite stable (MSS) cancers. The aim of this study was to determine the phenotype of this unique lymphocyte population in MSI and MSS colorectal cancers. Twenty-four individuals with sporadic colorectal cancer (17 MSI, 7 MSS) were included in this study. Intraepithelial and stromal lymphocytes were detected using immunohistochemistry with anti-CD8 and anti-CD103 antibodies, and two observers independently quantified the numbers of lymphocytes. CD103+ (alpha E beta 7+) IELs detected within tumour tissue co-expressed CD8+ while the stromal lymphocytes were phenotypically heterogeneous, with respect to CD8+ and CD103+ expression. MSI colorectal cancers harboured increased numbers of CD8+ CD103+ IELs, as well as CD8+ CD103- and CD8+ CD103+ stromal lymphocytes, when compared with MSS colorectal cancers. CD103+ IELs were found at 27-fold greater numbers in the tumour epithelium than in normal epithelium from the same patient (P = 0.001, Wilcoxon matched pairs test). From our findings, we have proposed a mechanism for the homing of these alpha E beta 7+ lymphocytes to tumour tissue in MSI and MSS colorectal cancers.