Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial.

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.

Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial.

BACKGROUND: Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer. METHODS: In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m(2) intravenous irinotecan every 3 weeks (300 mg/m(2) if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876. RESULTS: Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12-13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83-1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64-0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 [21]% vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group. INTERPRETATION: Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents. FUNDING: Cancer Research UK, Amgen Inc.

Evaluation of outcome measures for use in clinical practice for adults with musculoskeletal conditions of the knee: a systematic review.

BACKGROUND: This systematic review reported on the clinimetric properties of outcome measures for use in clinical practice for adults with musculoskeletal conditions of the knee. METHODS: A systematic search was performed in Medline, EMBASE, Cinahl and AMED to identify studies examining the clinimetric properties of outcome measures for adults undergoing conservative treatment of ligament injuries, meniscal lesions, patellofemoral pain and osteoarthritis of the knee. Outcomes measures taking less than 20 min to administer and requiring minimal equipment and space were included. Pairs of authors used a checklist to record the characteristics of the outcome measures, their reported clinimetric properties and the demographics of the study populations. The OMERACT filters of 'truth' and 'discrimination' were applied to the data for each outcome measure by an expert panel. RESULTS: Forty-seven studies were included evaluating 37 outcome measures. Ten outcome measures had adequate supporting evidence for 'truth' and 'discrimination': AAOS, AKPS, goniometer measurement, IKDC, KOOS, LEFS, Lysholm, Tegner, WOMAC and WOMET. However none of the outcome measures had been comprehensively tested across all clinimetric properties. CONCLUSION: Despite the widespread use of some outcome measures in clinical practice and primary research, data on the clinimetric properties were available for only 37 and of these only 10 had adequate supporting evidence for use in this population. However, before a core set of outcome measures can be recommended use in clinical practice, for adults with musculoskeletal conditions of the knee, consensus should be obtained on 'feasibility' in terms of burden on the clinician and the participant.

Exercise for preventing and treating osteoporosis in postmenopausal women.

BACKGROUND: Osteoporosis is a condition resulting in an increased risk of skeletal fractures due to a reduction in the density of bone tissue. Treatment of osteoporosis typically involves the use of pharmacological agents. In general it is thought that disuse (prolonged periods of inactivity) and unloading of the skeleton promotes reduced bone mass, whereas mechanical loading through exercise increases bone mass. OBJECTIVES: To examine the effectiveness of exercise interventions in preventing bone loss and fractures in postmenopausal women. SEARCH STRATEGY: During the update of this review we updated the original search strategy by searching up to December 2010 the following electronic databases: the Cochrane Musculoskeletal Group's Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010 Issue 12); MEDLINE; EMBASE; HealthSTAR; Sports Discus; CINAHL; PEDro; Web of Science; Controlled Clinical Trials; and AMED. We attempted to identify other studies by contacting experts, searching reference lists and searching trial registers. SELECTION CRITERIA: All randomised controlled trials (RCTs) that met our predetermined inclusion criteria. DATA COLLECTION AND ANALYSIS: Pairs of members of the review team extracted the data and assessed trial quality using predetermined forms. For dichotomous outcomes (fractures), we calculated risk ratios (RRs) using a fixed-effect model. For continuous data, we calculated mean differences (MDs) of the percentage change from baseline. Where heterogeneity existed (determined by the I(2) statistic), we used a random-effects model. MAIN RESULTS: Forty-three RCTs (27 new in this update) with 4320 participants met the inclusion criteria. The most effective type of exercise intervention on bone mineral density (BMD) for the neck of femur appears to be non-weight bearing high force exercise such as progressive resistance strength training for the lower limbs (MD 1.03; 95% confidence interval (CI) 0.24 to 1.82). The most effective intervention for BMD at the spine was combination exercise programmes (MD 3.22; 95% CI 1.80 to 4.64) compared with control groups. Fractures and falls were reported as adverse events in some studies. There was no effect on numbers of fractures (odds ratio (OR) 0.61; 95% CI 0.23 to 1.64). Overall, the quality of the reporting of studies in the meta-analyses was low, in particular in the areas of sequence generation, allocation concealment, blinding and loss to follow-up. AUTHORS' CONCLUSIONS: Our results suggest a relatively small statistically significant, but possibly important, effect of exercise on bone density compared with control groups. Exercise has the potential to be a safe and effective way to avert bone loss in postmenopausal women.

Perceived academic quality and approaches to studying in the health professions.

BACKGROUND: Students in higher education may adopt different approaches to studying, depending upon their perceptions of the academic quality of their courses and programmes, and both are likely to depend upon the nature of the curricula to which they are exposed. AIMS: Perceptions of quality and approaches to studying were investigated in students taking pre-registration programmes in a school of health professions. Two of the programmes were 3-year undergraduate programmes with subject-based curricula, and two were 2-year entry-level masters programmes with problem-based curricula. METHOD: The Course Experience Questionnaire (CEQ) and the Revised Approaches to Studying Inventory (RASI) were administered to the students within a single survey. Their teachers were also surveyed with regard to their beliefs and intentions about teaching. RESULTS: The teachers on the two kinds of programme exhibited similar beliefs and intentions about teaching. However, the students on the masters programmes produced higher ratings than did the students on the undergraduate programmes with regard to the appropriateness of their assessment, the acquisition of generic skills and the emphasis on student independence. The students on the masters programmes were also more likely to show a deep approach to studying and less likely to show a surface approach to studying than were the students on the undergraduate programmes. CONCLUSIONS: The CEQ and the RASI provide complementary evidence for use in research, in quality assurance and in quality enhancement. In comparison with subject-based curricula, problem-based curricula seem to enhance students' perceptions of their programmes and the quality of their learning.