Indicators are Relational: Navigating Knowledge and Power in the Development and Implementation of Coastal-Marine Indicators.

In many environment and resource management contexts (e.g., integrated coastal management, ecosystem-based fisheries management), indicator selection and development are perceived as a largely technical, bureaucratic, and scientific challenge. As such, choices about indicators and their application are often treated as external from everyday politics and dynamics of social power. Our aim here is to highlight the value of a relational perspective that weaves power and knowledge together in the context of indicator development and implementation. We highlight four critical dimensions of this relational perspective that may lead to better indicator process outcomes: 1) centering identity and positionality to reflect power differentials; 2) emphasizing the importance of indicator 'fit' and the politics of scale; 3) engaging rather than erasing social-ecological complexity; and 4) reflecting on social norms and relationships to foster adaptation and learning. These four dimensions are rarely considered in most indicator initiatives, including those that are more participatory in design and implementation. The dimensions we outline here emerge from the grounded experience of managers and practitioners, including indicator processes in which we are currently engaged, as well as a scoping review of the literature on indicators for coastal and marine governance and conservation specifically. However, the four dimensions and relational focus are relevant to a wide range of resource and environmental management contexts and provide a pathway to catalyze more effective indicator processes for decision-making and governance more generally.

Staufen 1 is expressed by neural precursor cells in the developing murine cortex but is dispensable for NPC self-renewal and neuronal differentiation in vitro.

BACKGROUND: Proper development of the cerebral cortex relies on asymmetric divisions of neural precursor cells (NPCs) to produce a recurring NPC and a differentiated neuron. Asymmetric divisions are promoted by the differential localization of cell-fate determinants, such as mRNA, between daughter cells. Staufen 1 (Stau1) is an RNA-binding protein known to localize mRNA in mature hippocampal neurons. Its expression pattern and role in the developing mammalian cortex remains unknown. RESULTS: Both stau1 mRNA and Stau1 protein were found to be expressed in all cells of the developing murine cortex. Stau1 protein expression was characterized spatially and temporally throughout cortical development and found to be present in all stages investigated. We observed expression in the nucleus, cytoplasm and distal processes of both NPCs and newly born neurons and found it to shuttle between the nucleus and the cytoplasm. Upon shRNA-mediated knock-down of Stau1 in primary cultures of the developing cortex, we did not observe any phenotype in NPCs. They were able to both self-renew and generate neurons in the absence of Stau1 expression. CONCLUSIONS: We propose that Stau1 is either dispensable for the development of the cerebral cortex or that its paralogue, Stau2, is able to compensate for its loss.

Impact of cigarette smoke and aerobic physical training on histological and molecular markers of prostate health in rats.

Recent evidence suggests that aerobic physical training may attenuate the deleterious effects of cancer risk factors, including smoking. We investigated the effects of cigarette smoke inhalation and aerobic physical training on the expression of steroid receptors and inflammatory and apoptotic proteins in the prostate. Forty male Wistar rats were distributed in four groups: control (CO), exercise (EXE), cigarette smoke exposure (CS), and cigarette smoke exposure with exercise (CS+EXE). For eight weeks, animals were repeatedly exposed to cigarette smoke for 30 min or performed aerobic physical training either with or without the cigarette smoke inhalation protocol. Following these experiments, we analyzed prostate epithelial morphology and prostatic expression of androgen (AR) and glucocorticoid receptors (GR), insulin-like growth factor (IGF-1), B-cell lymphoma-2 (BCL-2), BCL-2-associated X protein (BAX), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-κB) via immunohistochemistry. Cigarette smoke exposure stimulated the expression of AR, IGF-1, BCL-2, and NF-κB while downregulating BAX, IL-6, and TNF-α labeling in the prostate. In contrast, aerobic physical training attenuated cigarette smoke-induced changes in AR, GR, IGF-1, BCL-2, IL-6, TNF-α, and NF-κB. This suggests that cigarette smoke stimulates inflammation and reduces apoptosis, culminating in increased prostatic epithelial and extracellular matrices, whereas physical training promoted beneficial effects towards maintaining normal prostate morphology and protein levels.

Impact of cigarette smoke and aerobic physical training on histological and molecular markers of prostate health in rats

Recent evidence suggests that aerobic physical training may attenuate the deleterious effects of cancer risk factors, including smoking. We investigated the effects of cigarette smoke inhalation and aerobic physical training on the expression of steroid receptors and inflammatory and apoptotic proteins in the prostate. Forty male Wistar rats were distributed in four groups: control (CO), exercise (EXE), cigarette smoke exposure (CS), and cigarette smoke exposure with exercise (CS+EXE). For eight weeks, animals were repeatedly exposed to cigarette smoke for 30 min or performed aerobic physical training either with or without the cigarette smoke inhalation protocol. Following these experiments, we analyzed prostate epithelial morphology and prostatic expression of androgen (AR) and glucocorticoid receptors (GR), insulin-like growth factor (IGF-1), B-cell lymphoma-2 (BCL-2), BCL-2-associated X protein (BAX), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-κB) via immunohistochemistry. Cigarette smoke exposure stimulated the expression of AR, IGF-1, BCL-2, and NF-κB while downregulating BAX, IL-6, and TNF-α labeling in the prostate. In contrast, aerobic physical training attenuated cigarette smoke-induced changes in AR, GR, IGF-1, BCL-2, IL-6, TNF-α, and NF-κB. This suggests that cigarette smoke stimulates inflammation and reduces apoptosis, culminating in increased prostatic epithelial and extracellular matrices, whereas physical training promoted beneficial effects towards maintaining normal prostate morphology and protein levels.

Resting metabolic rate prediction equations and the validity to assess energy deficiency in the athlete population.

NEW FINDINGS: What is the topic of this review? We review the issues with using predicted resting metabolic rate equations in athletic populations. What advances does it highlight? The use of dated predicted resting metabolic rate equations is not appropriate for athletic populations until more studies have been conducted among these unique populations. ABSTRACT: Resting metabolic rate (RMR) is the amount of energy the body uses at rest. A suppressed RMR has been correlated with low energy availability and therefore used as an indicator of an individual's energy state. Furthermore, confounding identification of low energy availability within an athletic population are the physiological measures required, which can be time consuming and require professional expertise. To negate the demands of laboratory protocols in measuring RMR, predicted RMR (p RMR) equations were developed. Caution should be exercised when applying the p RMR equations for determining low energy availability in athletes owing to the population used to develop the equations and the higher metabolic cost of fat-free mass, thus elevated RMR, associated with athletes. Moreover, a low ratio of measured RMR to p RMR is often used as an alternative marker for energy deficiency. Predictive equations should implement fat-free mass within the algorithm when estimating RMR in athletic populations. The purpose of this paper is to describe p RMR equation development and the issues associated with use of p RMR equations for athletic populations. As professional sport increases, validation of p RMR equations in the modern athlete population is needed to monitor energy availability for athletic health and performance.

Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer.

The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3-1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.

Comparison of treatment and outcome information between a clinical trial and the National Cancer Data Repository.

BACKGROUND: Clinical trials are important but many factors limit their success, including the costs of long-term follow-up and participants often not being representative of the general population. The National Cancer Data Repository (NCDR) contains data about patients with cancer in England that may help overcome some of these problems. This study compared treatment and outcome information between the Medical Research Council Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (CLASICC) trial and the NCDR. METHODS: Participants in the CLASICC trial were identified in the NCDR, and management and outcome data were compared. Data on all surgically treated English patients with colorectal cancer were extracted from the NCDR and compared with those of CLASICC participants. RESULTS: Survival and treatment data for those in the CLASICC trial were available in the NCDR for 98·9 and 95·8 per cent of patients respectively. There was agreement in operation type for 86·1 per cent of patients but surgical approach coding was poor, with only 58·4 per cent of laparoscopic procedures coded in the NCDR. There was no significant difference in survival calculated from either data set. Surgical information was available in the NCDR for 19 of 20 trial participants with missing data. The trial population was younger (P < 0·001), of better socioeconomic status (P = 0·001) and with earlier disease (P < 0·001) than the general surgically treated colorectal cancer population. Rectal cancer survival was similar, but 5-year survival after treatment of colonic cancer was significantly better in the trial than in the national data: 57·1 (95 per cent confidence interval 51·5 to 62·3) versus 49·8 (49·3 to 50·2) per cent respectively. CONCLUSION: The National Cancer Data Repository demonstrates potential for informing clinical trials, but limitations prevent full intention-to-treat analyses.

Five-year follow-up of the Medical Research Council CLASICC trial of laparoscopically assisted versus open surgery for colorectal cancer.

INTRODUCTION: The UK Medical Research Council CLASICC trial assessed the safety and efficacy of laparoscopically assisted surgery in comparison with open surgery for colorectal cancer. The results of the 5-year follow-up analysis are presented. METHODS: Five-year outcomes were analysed and included overall and disease-free survival, and local, distant and wound/port-site recurrences. Two exploratory analyses were performed to evaluate the effect of age (70 years or less, or more than 70 years) on overall survival between the two groups, and the effect of the learning curve. RESULTS: No differences were found between laparoscopically assisted and open surgery in terms of overall survival, disease-free survival, and local and distant recurrence. Wound/port-site recurrence rates in the laparoscopic arm remained stable at 2.4 per cent. Conversion to open operation was associated with significantly worse overall but not disease-free survival, which was most marked in the early follow-up period. The effect of surgery did not differ between the age groups, and surgical experience did not impact on the 5-year results. CONCLUSION: The 5-year analyses confirm the oncological safety of laparoscopic surgery for both colonic and rectal cancer. The use of laparoscopic surgery to maximize short-term outcomes does not compromise the long-term oncological results. REGISTRATION NUMBER: ISRCTN74883561 (http://www.controlled-trials.com).

The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer.

BACKGROUND: Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups. METHODS: In total, 205 patients received neoadjuvant CT+/-ZOL (CT+ZOL, n=102; CT, n=103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n=195), outcome differences between groups were assessed adjusting for potential response modifiers. RESULTS: Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT+ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95% confidence interval: 3.5-20.4 mm; P=0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT+ZOL group (P=0.146). There was no difference in axillary nodal involvement (P=0.6315). CONCLUSION: These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.

Adhesions and incisional hernias following laparoscopic versus open surgery for colorectal cancer in the CLASICC trial.

BACKGROUND: This study investigated adhesive intestinal obstruction (AIO) and incisional hernia (IH) in patients undergoing laparoscopically assisted and open surgery for colorectal cancer. METHODS: In a case-note review of patients randomized to the Medical Research Council's Conventional versus Laparoscopic-Assisted Surgery In Colorectal Cancer (CLASICC) trial, primary and key secondary endpoints were AIO and IH admission rates respectively. RESULTS: Of 411 patients, 11 were admitted for AIO: four (3.1 per cent) of 131 patients in the open arm of the trial versus seven (2.5 per cent) of 280 in the laparoscopic arm (difference 0.6 (95 per cent confidence interval (c.i.) - 2.9 to 4.0) per cent). Thirty-six patients developed IH: 12 (9.2 per cent) after open versus 24 (8.6 per cent) after laparoscopic surgery (difference 0.6 (95 per cent c.i. - 5.3 to 6.5) per cent). Results by actual procedure showed higher AIO and IH rates in the 24.5 per cent of patients who converted from laparoscopic to open surgery (AIO: 2.3, 2.0 and 6 per cent; IH: 8.6, 7.4 and 11 per cent-for open, laparoscopic and converted operations respectively). CONCLUSION: Although this study has not confirmed that laparoscopic surgery reduces rates of AIO and IH after colorectal cancer surgery, trends suggest that a reduction in conversion to open surgery and elimination of port-site hernias may produce such an effect. Registration number for CLASICC trial: ISRCTN74883561 (http://www.controlled-trials.com).

Tree mortality following partial harvests is determined by skidding proximity.

Recently developed structural retention harvesting strategies aim to improve habitat and ecological services provided by managed forest stands by better emulating natural disturbances. The potential for elevated mortality of residual trees following such harvests remains a critical concern for forest managers, and may present a barrier to more widespread implementation of the approach. We used a harvest chronosequence combined with dendrochronological techniques and an individual-based neighborhood analysis to examine the rate and time course of residual-tree mortality in the first decade following operational partial "structural retention" harvests in the boreal forest of Ontario, Canada. In the first year after harvest, residual-tree mortality peaked at 12.6 times the preharvest rate. Subsequently, mortality declined rapidly and approached preharvest levels within 10 years. Proximity to skid trails was the most important predictor both of windthrow and standing death, which contributed roughly equally to total postharvest mortality. Local exposure further increased windthrow risk, while crowding enhanced the risk of standing mortality. Ten years after harvest, an average of 10.5% of residual trees had died as a result of elevated postharvest mortality. Predicted cumulative elevated mortality in the first decade after harvest ranged from 2.4% to 37% of residual trees across the observed gradient of skid trail proximity, indicating that postharvest mortality will remain at or below acceptable rates only if skidding impacts are minimized. These results represent an important step toward understanding how elevated mortality may influence stand dynamics and habitat supply following moderate-severity disturbances such as partial harvests, insect outbreaks, and windstorms.

Timing of breast cancer surgery in relation to menstrual cycle phase: no effect on 3-year prognosis: the ITS Study.

The effect of breast cancer surgery timing during the menstrual cycle on prognosis remains controversial. We conducted a multicentre prospective study to establish whether timing of interventions influences prognosis. We report 3-year overall and disease-free survival (OS/DFS) results for 'primary analysis' patients (regular cycles, no oral contraceptives within previous 6 months). Data were collected regarding timing of interventions in relation to patients' last menstrual period (LMP) and first menstrual period after surgery (FMP). Hormone profiles were also measured. Cox's proportional hazards model incorporated LMP in continuous form. Exploratory analyses used menstrual cycle categorisations of Senie, Badwe and Hrushesky. Hormone profiles with LMP and FMP data were also used to define menstrual cycle phase. Four hundred and twelve 'primary analysis' patients were recruited. Three-year OS from first surgery was 90.7, 95% confidence interval (CI) [87.9, 93.6%]. Menstrual cycle according to LMP was not statistically significant (OS: hazard ratio (HR)=1.02, 95%CI [0.995,1.042], P=0.14; DFS: HR=1.00, 95%CI [0.980,1.022], P=0.92). Timing of surgery in relation to menstrual cycle phase had no significant impact on 3-year survival. This may be due to 97% of patients receiving some form of adjuvant therapy. Survival curves to 10 years indicate results may remain true for longer-term survival.

Patient factors influencing conversion from laparoscopically assisted to open surgery for colorectal cancer.

BACKGROUND: Intraoperative conversion from laparoscopically assisted to open surgery for colorectal cancer is thought to be influenced by several patient factors. Analysis of the Conventional versus Laparoscopic-Assisted Surgery In Colorectal Cancer (CLASICC) Trial data aimed to identify these risk factors. METHODS: Of 488 laparoscopically assisted procedures attempted, 143 (29.3 per cent) were converted to open operation. Patient factors considered in multivariable analyses were age, sex, previous abdominal incisions, body mass index (BMI), tumour site, tumour diameter, pathological tumour (pT) and pathological node (pN) stage, extent of tumour spread from the muscularis propria, liver and peritoneal metastases, and American Society of Anesthesiologists (ASA) grade. As BMI was missing for 30.7 per cent of patients, two approaches were employed: one considered BMI as a possible risk factor and one did not. RESULTS: When BMI was taken into consideration, male sex (odds ratio (OR) 2.07; P = 0.020), BMI (OR 1.10; P = 0.006) and extent of tumour spread from the muscularis propria (OR 1.08; P < 0.001) were independent predictors of conversion. When BMI was not considered, extent of tumour spread (OR 1.07; P < 0.001) and male sex (OR 2.05; P = 0.004) were again identified, as were tumour site (OR 2.11; P = 0.005) and ASA grade (II versus I, OR 0.92; III versus I, OR 2.74; P = 0.012). CONCLUSION: Intraoperative conversion is more likely with larger BMI, in men, patients with rectal cancer, those graded ASA III or when there is greater local tumour spread.

Closeness to death and quality of life in advanced lung cancer patients.

AIMS: It has been recommended that closeness to death is considered when designing and reporting quality-of-life (QoL) studies in patients with advanced cancer. The aim of this work was to assess whether this finding holds when adjusting for previous QoL. MATERIALS AND METHODS: The study sample comprised 107 advanced non-small cell lung cancer patients randomised to the Big Lung Trial-QoL Study. Baseline and week 12 QoL data and patient characteristics were considered. Univariate and multivariate analysis of week 12 QoL considered baseline QoL scores, closeness to death, patient characteristics and treatment. RESULTS: Univariate analyses showed significantly different week 12 QoL according to closeness to death for nine of 15 QoL domains. Multivariate analyses showed closeness to death to be independently predictive of only three QoL domains, with performance status and baseline QoL being more predominant. CONCLUSIONS: In the present study, closeness to death was not found to be as important a factor in multivariate analysis as previously found. We recommend that previous QoL and performance status are considered in the design and analysis of QoL studies in which QoL is assessed at multiple time points in patients with advanced cancer, and that closeness to death may also be considered.

Short-term costs of conventional vs laparoscopic assisted surgery in patients with colorectal cancer (MRC CLASICC trial).

The short-term clinical results of the CLASICC trial indicated that clinical outcomes were similar between laparoscopic and open approaches. This study presents the short-term (3 month) cost analysis undertaken on a subset of patients entered into the CLASICC trial (682 of 794 patients). As expected the costs associated with the operation were higher in the 452 patients randomised to laparoscopic surgery (lap) compared with the 230 randomised to open procedure (open), Pounds 1703 vs Pounds 1386. This was partially offset by the other hospital (nontheatre) costs, which were lower in the lap group (Pounds 2930 vs Pounds 3176). The average cost to individuals for reoperations was higher in the lap group (Pounds 762 vs Pounds 553). Overall costs were slightly higher in the lap group (Pounds 6899 vs Pounds 6631), with mean difference of Pounds 268 (95%CI -689 to 1457). Sensitivity analysis made little difference to these results. The cost of rectal surgery was higher than for colon, for lap (Pounds 8259 vs Pounds 5586) and open procedures (Pounds 7820 vs Pounds 5503). The short-term cost analysis for the CLASICC trial indicates that the costs of either laparoscopic or open procedure were similar, lap surgery costing marginally more on average than open surgery.

Assessment of quality of life in the supportive care setting of the big lung trial in non-small-cell lung cancer.

PURPOSE: The Big Lung Trial (BLT) was a large, pragmatic trial to evaluate the addition of chemotherapy to primary treatment (ie, surgery, radical radiotherapy, or supportive care) in non-small-cell lung cancer (NSCLC). In the supportive care group, there was a small but significant survival benefit in patients treated with chemotherapy compared with supportive care alone (no chemotherapy). A substudy was undertaken to evaluate the quality of life (QoL) implications of the treatment options. QoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires C30 (QLQ-C30) and LC17, and daily diary cards. PATIENTS AND METHODS: EORTC QLQ-C30 and LC17 were collected at 0, 6 to 8, 12, 18, and 24 weeks. Diary cards were completed during the first 12 weeks of the study. The primary end point was global QoL at 12 weeks. RESULTS: A total of 273 patients were randomly assigned: 138 to no chemotherapy and 135 to chemotherapy. There was no evidence of a large detrimental effect on QoL of chemotherapy. No statistically significant differences in global QoL or physical/emotional functioning, fatigue and dyspnea, and pain were detected at 12 weeks. Higher rates of palliative radiotherapy in the no chemotherapy arm may have lessened differences in QoL. Global QoL, role functioning, fatigue, appetite loss, and constipation were prognostic indicators of survival at 12 weeks. CONCLUSION: There were no important adverse effects of chemotherapy on QoL.

Bladder and sexual function following resection for rectal cancer in a randomized clinical trial of laparoscopic versus open technique.

BACKGROUND: Bladder and sexual dysfunction are recognized complications of mesorectal resection. Their incidence following laparoscopic surgery is unknown. METHODS: Bladder and sexual function were assessed in patients who had undergone laparoscopic rectal, open rectal or laparoscopic colonic resection as part of the UK Medical Research Council Conventional versus Laparoscopic-Assisted Surgery In Colorectal Cancer (CLASICC) trial, using the International Prostatic Symptom Score, the International Index of Erectile Function and the Female Sexual Function Index. Sexual and bladder function data from the European Organization for Research and Treatment of Cancer QLQ-CR38 collected in the CLASICC trial were used for comparison. RESULTS: Two hundred and forty-seven (71.2 per cent) of 347 patients completed questionnaires. Bladder function was similar after laparoscopic and open rectal operations for rectal cancer. Overall sexual function and erectile function tended to be worse in men after laparoscopic rectal surgery than after open rectal surgery (overall function: difference - 11.18 (95 per cent confidence interval (c.i.) -22.99 to 0.63), P = 0.063; erectile function: difference -5.84 (95 per cent c.i. -10.94 to -0.74), P = 0.068). Total mesorectal excision (TME) was more commonly performed in the laparoscopic rectal group than in the open rectal group. TME (odds ratio (OR) 6.38, P = 0.054) and conversion to open operation (OR 2.86, P = 0.041) were independent predictors of postoperative male sexual dysfunction. No differences were detected in female sexual function. CONCLUSION: Laparoscopic rectal resection did not adversely affect bladder function, but there was a trend towards worse male sexual function. This may be explained by the higher rate of TME in the laparoscopic rectal resection group.

Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life.

BACKGROUND: In 1995 a meta-analysis of randomised trials investigating the value of adding chemotherapy to primary treatment for non-small cell lung cancer (NSCLC) suggested a small survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings. However, the meta-analysis included many small trials and trials with differing eligibility criteria and chemotherapy regimens. METHODS: The aim of the Big Lung Trial was to confirm the survival benefits seen in the meta-analysis and to assess quality of life and cost in the supportive care setting. A total of 725 patients were randomised to receive supportive care alone (n = 361) or supportive care plus cisplatin-based chemotherapy (n = 364). RESULTS: 65% of patients allocated chemotherapy (C) received all three cycles of treatment and a further 27% received one or two cycles. 74% of patients allocated no chemotherapy (NoC) received thoracic radiotherapy compared with 47% of the C group. Patients allocated C had a significantly better survival than those allocated NoC: HR 0.77 (95% CI 0.66 to 0.89, p = 0.0006), median survival 8.0 months for the C group v 5.7 months for the NoC group, a difference of 9 weeks. There were 19 (5%) treatment related deaths in the C group. There was no evidence that any subgroup benefited more or less from chemotherapy. No significant differences were observed between the two groups in terms of the pre-defined primary and secondary quality of life end points, although large negative effects of chemotherapy were ruled out. The regimens used proved to be cost effective, the extra cost of chemotherapy being offset by longer survival. CONCLUSIONS: The survival benefit seen in this trial was entirely consistent with the NSCLC meta-analysis and subsequent similarly designed large trials. The information on quality of life and cost should enable patients and their clinicians to make more informed treatment choices.

Control of directionality in the site-specific recombination system of the Streptomyces phage phiC31.

The genome of the Streptomyces temperate phage phiC31 integrates into the host chromosome via a recombinase belonging to a novel group of phage integrases related to the resolvase/invertase enzymes. Previously, it was demonstrated that, in an in vitro recombination assay, phiC31 integrase catalyses integration (attP/attB recombination) but not excision (attL/attR). The mechanism responsible for this recombination site selectivity was therefore investigated. Purified integrase was shown to bind with similar apparent binding affinities to between 46 bp and 54 bp of DNA at each of the attachment sites, attP, attB, attL and attR. Assays using recombination sites of 50 bp and 51 bp for attP and attB, respectively, showed that these fragments were functional in attP/attB recombination and maintained strict site selectivity, i.e. no recombination between non-permissive sites, such as attP/attP, attB/attL, etc., was observed. Using bandshifts and supershift assays in which permissive and non-permissive combinations of att sites were used in the presence of integrase, only the attP/attB combination could generate supershifts. Recombination products were isolated from the supershifted complexes. It was concluded that these supershifted complexes contained the recombination synapse and that site specificity, and therefore directionality, is determined at the level of stable synapse formation.

In vitro site-specific integration of bacteriophage DNA catalyzed by a recombinase of the resolvase/invertase family.

The genome of the broad host range Streptomyces temperate phage, phiC31, is known to integrate into the host chromosome via an enzyme that is a member of the resolvase/invertase family of site-specific recombinases. The recombination properties of this novel integrase on the phage and Streptomyces ambofaciens attachment sites, attP and attB, respectively, were investigated in the heterologous host, Escherichia coli, and in an in vitro assay by using purified integrase. The products of attP/B recombination, i.e., attL and attR, were identical to those obtained after integration of the prophage in S. ambofaciens. In the in vitro assay only buffer, purified integrase, and DNAs encoding attP and attB were required. Recombination occurred irrespective of whether the substrates were supercoiled or linear. A mutant integrase containing an S12F mutation was completely defective in recombination both in E. coli and in vitro. No recombination was observed between attB/attB, attP/attP, attL/R, or any combination of attB or attP with attL or attR, suggesting that excision of the prophage (attL/R recombination) requires an additional phage- or Streptomyces-encoded factor. Recombination could occur intramolecularly to cause deletion between appropriately orientated attP and attB sites. The results show that directionality in phiC31 integrase is strictly controlled by nonidentical recombination sites with no requirement to form the topologically defined structures that are more typical of the resolvases/invertases.