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Background Cancer cachexia causes significant morbidity and mortality in advanced lung cancer patients. Clinical benefit of β-hydroxy-β-methylbutyrate, arginine, and glutamine (HMB/Arg/Gln) was assessed in newly diagnosed patients. Methods NOURISH, a prospective, two-arm, open-label, multi-centre, randomised controlled phase II trial compared cachexia in patients who received HMB/Arg/Gln with those who did not. All patients received structured nutritional, exercise and symptom control via a Macmillan Durham Cachexia Pack. Conducted in five UK centres, patients aged > 18 years, with newly diagnosed advanced small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), who were able to take oral nutrition, with a performance status of 0-to-2 and a life expectancy > 4 months were eligible for trial entry. Patients suitable for treatment with curative intent were ineligible. The trial was designed as a signal-seeking pilot study with target recruitment of 96 patients. One-to-one randomisation was stratified by diagnosis (SCLC or NSCLC), stage of disease (locally advanced or metastatic) and performance status. The primary outcome measure was treatment success defined as a patient being alive without significant loss of lean body mass (not > 5%) by 12 weeks. Secondary outcome measures included quality of life. Results Between February-2012 and February-2013, 38 patients were recruited, 19 to each arm. Baseline characteristics were balanced. The trial was halted due to slow accrual and partial adherence. Trial data demonstrated no evidence of treatment benefit. No serious adverse events were reported during the trial. Conclusions Further evaluation of HMB/Arg/Gln in this setting could not be recommended on the basis of this trial. Clinical trial registration ISRCTN registry: 39911673; 14-Apr-2011 10.1186/ISRCTN39911673.

No abstract available.

This conceptual paper suggests that the distinction between an autocratic and democratic leadership orientation may serve as an important moderator of the relationship between key organizational characteristics and workplace bullying. More specifically, we explore leader autocratic vs. democratic power orientations and leader agentic vs. communal orientations as the theoretical bases for developing a new model of perceived leadership orientation as a moderator of the relationships between certain key organizational characteristics and perceptions of workplace bullying behavior. Our model proposes differential moderating effects for both leader autocratic-democratic power orientation and leader agentic-communal orientation. Particularly, we contend that democratic and communal leadership orientations may lead to fewer perceptions of bullying in the workplace. We conclude with a discussion of our model’s practical implications and suggestions for future research on this subject.

Importance Perioperative chemotherapy and surgery are a standard of care for operable gastroesophageal adenocarcinoma. Anti-HER2 therapy improves survival in patients with advanced HER2-positive disease. The safety and feasibility of adding lapatinib to perioperative chemotherapy should be assessed. Objectives To assess the safety of adding lapatinib to epirubicin, cisplatin, and capecitabine (ECX) chemotherapy and to establish a recommended dose regimen for a phase 3 trial. Design, Setting, and Participants Phase 2 randomized, open-label trial comparing standard ECX (sECX: 3 preoperative and 3 postoperative cycles of ECX with modified ECX plus lapatinib (mECX+L). This multicenter national trial was conducted in 29 centers in the United Kingdom in patients with histologically proven, HER2-positive, operable gastroesophageal adenocarcinoma. Registration forERBB/HER2testing took place from February 25, 2013, to April 19, 2016, and randomization took place between May 24, 2013, and April 21, 2016. Data were analyzed May 10, 2017, to May 25, 2017. Interventions Patients were randomized 1:1 open-label to sECX (3 preoperative and 3 postoperative cycles of 50 mg/m2of intravenous epirubicin on day 1, 60 mg/m2intravenous cisplatin on day 1, 1250 mg/m2 of oral capecitabine on days 1 through 21) or mECX+L (ECX plus lapatinib days 1 through 21 in each cycle and as 6 maintenance doses). The first 10 patients in the mECX+L arm were treated with 1000 mg/m2of capecitabine and 1250 mg of lapatinib per day, after which preoperative toxic effects were reviewed according to predefined criteria to determine doses for subsequent patients. Main Outcomes and Measures Proportion of patients experiencing grade 3 or 4 diarrhea with mECX+L. A rate of 20% or less was considered acceptable. No formal comparison between arms was planned. Results Between February 2013, and April 2016, 441 patients underwent central HER2 testing and 63 (14%) were classified as HER2 positive. Forty-six patients were randomized; 44 (24 sECX, 20 mECX+L) are included in this analysis. Two of the first 10 patients in the mECX+L arm reported preoperative grade 3 diarrhea; thus, no dose increase was made. The primary endpoint of preoperative grade 3 or 4 diarrhea rates were 0 of 24 in the sECX arm (0%) and 4 of 20 in the mECX+L arm (21%). One of 24 in the sECX arm and 3 of 20 in the mECX+L arm stopped preoperative treatment early, and for 4 of 19 in the mECX+L arm, lapatinib dose was reduced. Postoperative complication rates were similar in each arm. Conclusions and Relevance Administration of 1250 mg of lapatinib per day in combination with ECX chemotherapy was feasible with some increase in toxic effects, which did not compromise operative management. Trial Registration ISRCTN.org identifier:46020948; clinicaltrialsregister.eu identifier:2006-000811-12

Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.

Purpose Treating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC. Patients and Methods Patients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity. Results Eight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups. Conclusion Pravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer.

A semi-structured, web-based questionnaire was developed to survey midwives (n = 241) employed by NHS Tayside, UK, to identify current practice and views on weight management of obese women during pregnancy and the puerperium. A total of 78 (32%) midwives submitted responses following email invitation. Most respondents (79%) reported always calculating women's body mass index (BMI) at booking, with 73% routinely explaining the BMI category. In terms of future practice for obese women, although few respondents (15%) currently offer personalised advice regarding weight management based on a woman's diet and physical activity levels, 77% of respondents thought such advice would be appropriate and 69% thought it could possibly be feasible to offer such advice. The respondents viewed weight management to be of importance and felt that universal advice is appropriate, but confidence in discussing weight management and knowledge of the subject was low. Strategies to improve midwife confidence and weight management services should include training, ongoing support and definition of the midwife's role within the multidisciplinary team to support practice in the future.

Purpose To compare gefitinib with placebo in chemotherapy naïve patients with advanced non–small-cell lung cancer (NSCLC) and poor performance status. Patients and Methods NSCLC patients (chemotherapy naïve, WHO performance status 2 or 3; unfit for chemotherapy; stage IIIB/IV) were randomly assigned to gefitinib (250 mg/d) plus best supportive care (BSC; n = 100) or placebo plus BSC (n = 101). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), quality of life (QOL), pulmonary symptom improvement (PSI), and safety. Correlation of gefitinib efficacy with EGFR gene copy number (fluorescent in situ hybridization [FISH]) was explored. Results Hazard ratios (HRs; gefitinib:placebo) were 0.82 (95% CI, 0.60 to 1.12; P = .217) for PFS and 0.84 (95% CI, 0.62 to 1.15; P = .272) for OS. As expected for this patient population, OS for both arms was poor, at about 3 months. ORRs were 6.0% (gefitinib) and 1.0% (placebo). QOL and PSI rates were 21.1% and 28.3% (gefitinib) and 20.0% and 28.3% (placebo), respectively. In EGFR FISH-positive patients (n = 32), HRs were 0.29 (95% CI, 0.11 to 0.73) for PFS and 0.44 (95% CI, 0.17 to 1.12) for OS. No unexpected adverse events occurred. Conclusion There was no statistically significant difference in PFS, OS, and ORRs after treatment with gefitinib or placebo, in the overall population; improvements in QOL and symptoms were similar in both groups. Tolerability profile of gefitinib was consistent with previous studies. PFS was statistically significantly improved for gefitinib-treated patients with EGFR FISH-positive tumors.

Acquisitions continue to be an important topic for management scholars and practitioners alike. Managers are actively involved in both sides of the acquisition equation (target and acquirer) from valuation (preacquisition) all the way through to integration (postacquisition). During this tumultuous period, it now appears that the top management team of a successful target firm is integral to postacquisition success. The authors examine the role that "imposed" changes placed on the newly acquired firm has on the retention of the top management team. The compulsory changes appear to be a key factor in the turnover of top management team members and thus diminish the value of the acquired firm. Furthermore, this study suggests that top management team turnover detrimentally affects postacquisition firm performance.

The complex global business environment has created a host of problems for managers, none of which is more difficult to address than bullying in the workplace. The rapid rate of change and the ever-increasing complexity of organizational environments of business throughout the world have increased the opportunity for bullying to occur more frequently. This article addresses the foundations of bullying by examining the ‘nature’ (i.e., bullying behavior influenced by the innate genetic make-up of an individual) and the ‘nurture’ (i.e., individuals learn to be bullies and environments allow the behavior to perpetuate) arguments for the occurrence of bullying behavior. In addition, guidelines are presented for managers in global organizations to use in assessing and monitoring bullying activities in global organizations.

Leaders do not necessarily have the best interests of the organization in mind when they make decisions. Many times, leaders treat their own personal goals as more important in relation to the goals of the organization and frequently adopt a short-term decision horizon. Thus, leaders become destructive and make decisions for their own good at the expense of the organization. This article examines the bully as a leader and how the bully creates a dysfunctional environment where the bullied, the observer, and the organization suffer negative impact due to the decisions made by the bully. The externalities of bullying (i.e., unintended explicit and/or implicit consequences of bullying activities on the members of the organization) are discussed to highlight the importance of examining the spillover impact of bullying activities in organizations. In addition, the authors propose a method to address the negative impact of those who engage in bullying on the organizational as a whole.

Published information on the effectiveness of bronchial thermoplasty (BT) for severe asthma in ‘real life’ patients is limited. We compared safety and efficacy outcomes 12 months post procedure in 10 clinic patients and 15 patients recruited to clinical trials of BT at the same centre. Baseline asthma severity was greater in the clinic group. Adverse events were similar. Clinical improvements occurred in 50% of the clinic patients compared with 73% of the research patients.

Malignant mesothelioma (MM) is an aggressive cancer of mesothelial cells of pleural and peritoneal cavities. In 85% of cases both pleural and peritoneal MM is caused by asbestos exposure. Although both are asbestos-induced cancers, the incidence of pleural MM is significantly higher (85%) than peritoneal MM (15%). It has been proposed that carcinogenesis is a result of asbestos-induced inflammation but it is not clear what contributes to the differences observed between incidences of these two cancers. We hypothesize that the observed differences in incidences of pleural and peritoneal MM are the result of differences in the direct response of these cell types to asbestos rather than to differences mediated by the in vivo microenvironment. To test this hypothesis we characterized cellular responses to asbestos in a controlled environment. We found significantly greater changes in genome-wide expression in response to asbestos exposure in pleural mesothelial cells as compared to peritoneal mesothelial cells. In particular, a greater response in many common genes (IL-8, ATF3, CXCL2, CXCL3, IL-6, GOS2) was seen in pleural mesothelial cells as compared to peritoneal mesothelial cells. Unique genes expressed in pleural mesothelial cells were mainly pro-inflammatory (G-CSF, IL-1β, IL-1α, GREM1) and have previously been shown to be involved in development of MM. Our results are consistent with the hypothesis that differences in incidences of pleural and peritoneal MM upon exposure to asbestos are the result of differences in mesothelial cell physiology that lead to differences in the inflammatory response, which leads to cancer.

Purpose – The purpose of this paper is to examine and develop a cross‐level model of the phenomenon of bullying at three levels (e.g. individual, group, and organizational).Design/methodology/approach – This is a theory‐based paper operationalizing transactional coping theory across three levels of an organization relative to bullying activities.Findings – There can be spillover from bullying from the dyadic level to other levels in the organization. While bullying is frequently discussed as an individual‐to‐individual phenomenon, the conflict can reverberate up to the group and organizational level. The interaction between the three levels needs to be taken into consideration when developing effective managerial plans to address the negative consequences of bullying.Research limitations/implications – Additional research is needed to address the interaction effect between all three levels that can be impacted by bullying acts. Without addressing the spillover from one level to another, remediation progra...

Why does bullying occur in an organization? How will the globalization of an organization facilitate the process and encourage bullying to occur in that organization? What can be done to reduce the level/impact of bullying in an organization that is in transition? These are the focal questions addressed in this paper. Reference Point Theory (RPT) is applied to the bullying phenomena in an effort to illustrate the various reference points that can be used by the bully, the bullied, ‘others’ in the global organizations, as well as the management of the organization. The divergent reference points used by individuals in the organization can encourage bullying to occur and make attempts to reduce the resulting conflict much more difficult to implement. The paper develops a process to reduce the level of bullying during the transition to global organization and to limit the impact of bullying events that do occur in the organization.

Bullying in organizations has become one the prime social phenomena which can have a direct as well as indirect impact on the productivity of employees and managers. While bullying is a part of the fabric of society, the rate of occurrence as well as the severity of bullying acts in the workplace is alarming. This paper puts forth a model that illustrates the triangular relationship and interaction between the three components in the bullying event: 1) the organizational environment and its impact on the occurrence of bullying activities; 2) the characteristics of those that bully; and 3) the characteristics of those being bullied (e.g., victims of bullying). These three interrelated issues form the triangle of bullying that is examined in this paper. This paper posits that a major source of many of the personnel relational problems faced in the workplace between coworker and coworker or manager and employees comes from bullies, just like the ones experienced on the childhood playground. Research shows that child bullies and those bullied as children have the potential to become adult bullies. Combine that with the complex, diverse, global business arena that creates high levels of stress, it is easy to understand why there is the possibility of boardroom/workplace bullies. "Bullying at work is claimed to be more crippling and devastating problem for employees than all other work related stress put together... " (Einarsen, 1999).

Summary Background Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer. Methods For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0–2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. Findings Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23–4·50, for gefitinib vs 3·67 months, 95% CI 2·97–4·37, for placebo; hazard ratio [HR] 0·90, 95% CI 0·74–1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference −8·61, 95% CI −14·49 to −2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI −2·33 to 7·72, n=231, p=0·293), dysphagia (−3·18, 95% CI −8·36 to 2·00, n=231, p=0·228), and eating (−4·11, 95% CI −9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23–1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07–1·37 in the placebo group; HR 0·80, 95% CI 0·66–0·96, p=0·020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3–4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023). Interpretation The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients. Funding Cancer Research UK.

Objective To evaluate the impact of a diet and physical activity intervention (BeWEL) on weight change in people with a body mass index >25 weight (kg)/height (m)2 at increased risk of colorectal cancer and other obesity related comorbidities. Design Multicentre, parallel group, randomised controlled trial. Setting Four Scottish National Health Service health boards. Participants 329 overweight or obese adults (aged 50 to 74 years) who had undergone colonoscopy after a positive faecal occult blood test result, as part of the national bowel screening programme, and had a diagnosis of adenoma confirmed by histopathology. 163 were randomised to intervention and 166 to control. Intervention Participants were randomised to a control group (weight loss booklet only) or 12 month intervention group (three face to face visits with a lifestyle counsellor plus monthly 15 minute telephone calls). A goal of 7% reduction in body weight was set and participants received a personalised energy prescription (2508 kJ (600 kcal) below that required for weight maintenance) and bodyweight scales. Motivational interviewing techniques explored self assessed confidence, ambivalence, and personal values concerning weight. Behavioural strategies included goal setting, identifying intentions of implementation, self monitoring of body weight, and counsellor feedback about reported diet, physical activity, and weight change. Main outcome measures The primary outcome was weight change over 12 months. Secondary outcomes included changes in waist circumference, blood pressure, fasting cardiovascular biomarkers, and glucose metabolism variables, physical activity, diet, and alcohol consumption. Results At 12 months, data on the primary outcome were available for 148 (91%) participants in the intervention group and 157 (95%) in the control group. Mean weight loss was 3.50 kg (SD 4.91) (95% confidence interval 2.70 to 4.30) in the intervention group compared with 0.78 kg (SD 3.77) (0.19 to 1.38) in the control group. The group difference was 2.69 kg (95% confidence interval 1.70 to 3.67). Differences between groups were significant for waist circumference, body mass index, blood pressure, blood glucose level, diet, and physical activity. No reported adverse events were considered to be related to trial participation. Conclusions Significant weight loss can be achieved by a diet and physical activity intervention initiated within a national colorectal cancer screening programme, offering considerable potential for risk reduction of disease in older adults. Trial registration Current Controlled Trials ISRCTN53033856.

Background Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second highest cause of cancer death in the UK. Most cases occur in people over 50 years and CRC often co-exists with other lifestyle related disorders including obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). These diseases share risk factors related to the metabolic syndrome including large body size, abnormal lipids and markers of insulin resistance indicating common aetiological pathways. Methods/Design This 3 year study will be a two-arm, multicentre, randomised controlled trial comparing the BeWEL lifestyle (diet, physical activity and behaviour change) programme against usual care. The pre-trial development will take 6 months and participants will be recruited over a 12 month period and undertake the intervention and follow up for 12 months (total 24 months recruitment and intervention implementation) with a further 6 months for data collection, analysis and interpretation. Four hundred and fifty two participants who have had a colorectal adenoma detected and removed (through the national colorectal screening programme) will provide 80% power to detect a weight loss of 7% over 12 months. Primary outcomes are changes in body weight and waist circumference. Secondary outcomes will include cardiovascular risk factors, psycho-social measures and intervention costs. Discussion The results from this study will enhance the evidence base for lifestyle change in patients at higher risk of chronic disease including obesity related cancers. International Standard Randomised Controlled Trials No: ISRCTN53033856

This paper explores millennial job seekers and their parental involvement in the job search process. Preliminary work on a scale to measure the “appropriateness” of certain job search behaviors is reported. Ten parental job search behaviors are identified. The appropriateness constructs of “mentoring” and “meddling” are developed and empirically tested. Results indicate that both meddling and mentoring are valid and initially useful constructs in examining the suitability of parental involvement in the job search process. The possible impact of parental involvement in the job search process is then discussed along with possible managerial responses.

Context Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. Objective To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. Design, Setting, and Patients The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. Interventions Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n=551) or gemcitabine (1000 mg/m2 intravenous infusion once a week for 3 of every 4 weeks) (n=537) for 6 months. Main Outcome Measures Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. Results Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(2)(1) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P

Background: Cigarette smokers with asthma are insensitive to short term inhaled corticosteroid therapy, but efficacy when given for a longer duration at different doses is unknown. Methods: Ninety five individuals with mild asthma were recruited to a multicentre, randomised, double blind, parallel group study comparing inhaled beclomethasone in doses of 400 µg or 2000 µg daily for 12 weeks in smokers and non-smokers. The primary end point was the change in morning peak expiratory flow (PEF). Secondary end points included evening PEF, use of reliever inhaler, number of asthma exacerbations, spirometric parameters, and asthma control score. Results: After 12 weeks of inhaled beclomethasone there was a considerable difference between the morning PEF measurements of smokers and non-smokers with asthma (–18 (95% CI –35 to –1), adjusted p = 0.035). Among those receiving 400 µg daily there was a difference between the mean (95% CI) morning PEF (l/min) in smokers and non-smokers (–25 (95% CI –45 to –4), adjusted p = 0.019) and in the number of asthma exacerbations (6 v 1 in smokers and non-smokers, respectively, p = 0.007). These differences were reduced between smokers and non-smokers receiving 2000 µg inhaled beclomethasone daily. Conclusions: Compared with non-smokers, smokers with mild persistent asthma are insensitive to the therapeutic effect of low dose inhaled corticosteroid treatment administered for a 12 week period. The disparity of the response between smokers and non-smokers appears to be reduced with high dose inhaled corticosteroid. These findings have important implications for the management of individuals with mild asthma who smoke.

Rhabdomyosarcomas are a heterogeneous group of tumors with respect to their molecular basis, degree of differentiation, histology, and clinical behavior. Because of the wide variation of tumor morphology, it is often difficult to distinguish between the distinct subtypes of rhabdomyosarcomas. By using cryosections of tumor specimens and immunohistochemistry, in the present study we show that strong expression of myogenin in rhabdomyosarcoma is associated with alveolar histology (P =

BACKGROUND Topotecan is a topoisomerase I inhibitor with activity against xenografts of childhood solid tumors and established clinical activity against neuroblastoma and rhabdomyosarcoma. We have studied the relationship between systemic exposure to and the antitumor activity of topotecan lactone (the active form of the drug) in the xenograft models. Furthermore, we determined whether the responses seen in these models occur at systemic exposure levels that are tolerable in children. METHODS Neuroblastoma xenografts derived from the tumors of six different patients were established subcutaneously in immune-deprived mice. Topotecan was administered by intravenous bolus injection 5 days a week for 2 consecutive weeks, repeated every 21 days for three cycles. The minimum daily doses that induced complete responses (CRs) and partial responses (PRs) were determined. Topotecan lactone pharmacokinetic studies were performed in both tumor-bearing and nontumor-bearing mice. RESULTS The minimum doses associated with CRs and PRs in four of the six neuroblastoma xenografts were 0.61 and 0.36 mg/kg body weight, respectively. The topotecan lactone single-day systemic exposures associated with these doses were 88 and 52 ng x hr/mL, respectively. There was an approximately sixfold difference in topotecan lactone systemic exposure (290 ng x hr/mL versus 52 ng x hr/mL) associated with achieving CRs in the least-sensitive and most-sensitive tumors, respectively. CONCLUSIONS Neuroblastoma xenografts are highly sensitive to topotecan therapy, and responses in mice are achieved at systemic exposures similar to those that are clinically effective and tolerable in children. These results support the concept of deriving preclinical data relating systemic exposure to antitumor activity in xenograft models. Such data may be valuable in making informed decisions regarding the clinical development of new agents.

This report evaluated 24 computer-aided decision support systems (DSS) that can support management decision-making in forest ecosystems. It compares the scope of each system, spatial capabilities, computational methods, development status, input and output requirements, user support availability, and system performance. Questionnaire responses from the DSS developers (who have sole responsibility for their content) provide the basis for four summary tables comparing system capabilities. The responses are also presented verbatim for reference. This evaluation aids potential users of decision support systems in determining which system most closely fulfills their needs.

Introduction and Objectives Bronchial thermoplasty involves the delivery of radio frequency energy to the airways during flexible bronchoscopy, and possibly exerts its effect by reduction of airway smooth muscle mass (1). Clinical trials of bronchial thermoplasty have shown benefits in the treatment of patients with moderate or severe asthma. We describe our experience of introducing bronchial thermoplasty into a severe asthma clinical service. Methods Funding was obtained from the Greater Glasgow and Clyde NHS Health Board to evaluate bronchial thermoplasty in the treatment of ten patients with moderate to severe asthma. Patients were assessed at the Difficult Asthma Clinic and selected for the procedure using criteria similar to those employed in clinical trials of bronchial thermoplasty. Patients on all forms of asthma medication were eligible for treatment including omalizumab and oral prednisolone. Procedures were performed by 2 physicians or by 1 physician and a nurse, using conscious sedation with alfentanyl and midazolam. One patient required deeper sedation [remifentanyl and propofol] due to a complicated medical history. Bronchial thermoplasty was administered in three sessions, treating the right lower lobe, the left lower lobe and both upper lobes respectively. Follow up is at 3 monthly intervals for both safety and efficacy outcomes. Results Between 2nd June 2011 and 30th April 2012, ten patients underwent bronchial thermoplasty in Glasgow [7 males, 3 females] (Table 1). Six patients were at Step 5 and four at Step 4 of the British Guideline on the Management of Asthma scale. 4/10 were taking oral prednisolone daily and 2/10 were receiving omalizumab treatment [for 4th year and 3rd year respectively]. Treatment sessions were largely uneventful and adverse effects were similar to those reported in clinical trials. To date, there has been a reduction in some asthma medications: two patients receiving omalizumab have successfully discontinued treatment; those taking oral steroids are being weaned off prednisolone. Conclusion Bronchial thermoplasty can be safely delivered in a clinical setting to patients with severe asthma. References Thomson NC, Bicknell S, Chaudhuri R Bronchial thermoplasty for severe asthma. Curr Opin Allergy Clin Immunol 2012; 12:241–248.

In Scotland 68.5% of men, 61.8% of women, 36.1% of boys, and 26.9% of girls are classified as overweight or obese.1 The cost of obesity and obesity related illnesses to the NHS in Scotland was estimated to be £171m (€190m; $273m) in 2001,2 and forecasts in England suggest that NHS expenditure attributable to these conditions could double between 2007 and 2050.3 Being obese at age 40 reduces life expectancy by 7.1 years for women and 5.8 years for men.4 Given the massive detrimental effect of obesity on health and wellbeing, all health professionals should know how obesity should be managed. This article summarises the most recent recommendations from the Scottish Intercollegiate Guidelines Network (SIGN) on the management of obesity.5 SIGN recommendations are based on systematic reviews of best available evidence, and the strength of the evidence is indicated as A, B, C, or D (figure⇓). Recommended best practice (“good practice points”), based on the clinical experience of the guideline development group, is also indicated (as GPP). Explanation of SIGN grades of recommendations ### Classification Use body mass index (BMI) to classify overweight or obesity in adults (B): Waist circumference may be used in addition to BMI to help assess the risk of obesity related comorbidities (C). Waist circumference cut-off values for an increased risk of obesity related health problems are: ### Prevention and identification of high risk groups

A 62-year-old woman with known pyruvate kinase deficiency and previous splenectomy in early adulthood was investigated for breathlessness. A chest radiograph demonstrated a right retro-cardiac mass and computed tomography/magnetic resonance imaging scans confirmed a 56 · 37 · 60 mm heterogeneous soft tissue mass in the right paravertebral region at the T9/T10 level (top and bottom). The provisional diagnosis was of a neurogenic tumour and surgical excision was planned. Her full blood count at the time was as follows: haemoglobin concentration 101 g/l, white cell count 10AE76 · 10/l, platelet count 660 · 10/l and mean cell volume 105AE9 fl. Bilirubin was 28 lmol/l. She had been transfusion independent. At thoracotomy the mass appeared very vascular and adherent to the ribs and vertebra without bony erosion and with no involvement of nerve roots. The mass was completely excised at thoracotomy and microscopically was composed of varying proportions of mature adipocytes mixed with haemopoietic tissue with normal maturation. Extramedullary haemopoiesis is typically (>90% of cases) found in the liver and spleen in the context of myelofibrosis or thalassaemia but can occur rarely in the paravertebral area, central nervous system, eye, lymph nodes, myocardium, lung and pleura. There have been four previous reports of extramedullary haemopoiesis affecting the paravertebral area associated with pyruvate kinase deficiency with one case leading to spinal cord compression.

A shared experience of developing countries is the compelling need to "catch up". Perhaps in no other area is this need so keenly felt as in education for the underdeveloped systems of education, a legacy of the colonial era, have proven to be incapable of making the necessary contribution to national and economic development. In an attempt to compensate for the past deprivations and inequities, policy makers seek to formulate and implement in their respective countries, educational policies which have as their goal the democratization of all levels of the education system. In these countries, in most instances, the democratization of higher education has created a demand so great that it has outstripped available supply. Further, it has given rise to the need to reconcile equality of access with the maintenance of standards of excellence. As a result, many countries have attempted this reconciliation through their selection procedures for admitting students to institutions of higher education (UNESCO Report, 1989). In developing countries national institutions of higher education face complex issues in the selection of students seeking admission. These issues are related directly to national education policies or emerge from the need of the institutions to be responsive both to societal demands and national priorities, within a context of resource constraints. This paper presents a discussion of some policy issues in the selection of students at the College of The Bahamas during the early period of its existence (The College is the sole state-funded institution for tertiary-level education in the Commonwealth of The Bahamas). Major issues examined were concerned with the reconciliation of: 1) equality of access with the maintenance of standards of excellence; 2) freedom of choice in programme selection (implicit in democratization) with the national imperatives of manpower needs. It will be the position of this paper that in developing countries, such as the Bahamas, issues in the selection of students for higher education emerge primarily from the national education policy which has as its goal the provision of equal higher education opportunities for all citizens. Selection issues come to the fore when the attempt is made by educational administrators to translate the broad principles of such a policy into practice. Often, the experience is that, when implemented, the policy has the opposite effect of that intended and, therefore, corrective action is considered necessary to redirect the goals of the policy or to redefine the policy itself.

Chromosome territories assume non-random positions in the interphase nucleus with gene-rich chromosomes localized toward the nuclear interior and gene-poor chromosome territories toward the nuclear periphery. Lamins are intermediate filament proteins of the inner nuclear membrane required for the maintenance of nuclear structure and function. Here, we show using whole-genome expression profiling that Lamin A/C or Lamin B2 depletion in an otherwise diploid colorectal cancer cell line (DLD1) deregulates transcript levels from specific chromosomes. Further, three-dimensional fluorescence in situ hybridization (3D-FISH) analyses of a subset of these transcriptionally deregulated chromosome territories revealed that the diploid chromosome territories in Lamin-depleted cells largely maintain conserved positions in the interphase nucleus in a gene-density-dependent manner. In addition, chromosomal aneuploidies were induced in ~25 % of Lamin A/C or Lamin B2-depleted cells. Sub-populations of these aneuploid cells consistently showed a mislocalization of the gene-rich aneuploid chromosome 19 territory toward the nuclear periphery, while gene-poor aneuploid chromosome 18 territory was mislocalized toward the nuclear interior predominantly upon Lamin B2 than Lamin A/C depletion. In addition, a candidate gene locus ZNF570 (Chr.19q13.12) significantly overexpressed upon Lamin B2 depletion was remarkably repositioned away from the nuclear lamina. Taken together, our studies strongly implicate an overarching role for Lamin B2 in the maintenance of nuclear architecture since loss of Lamin B2 relieves the spatial positional constraints required for maintaining conserved localization of aneuploid chromosome territories in the interphase nucleus. Electronic supplementary material The online version of this article (doi:10.1007/s00412-016-0580-y) contains supplementary material, which is available to authorized users.