Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial.

Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64.

Pollinator adaptation and the evolution of floral nectar sugar composition.

A long-standing debate concerns whether nectar sugar composition evolves as an adaptation to pollinator dietary requirements or whether it is 'phylogenetically constrained'. Here, we use a modelling approach to evaluate the hypothesis that nectar sucrose proportion (NSP) is an adaptation to pollinators. We analyse ~ 2100 species of asterids, spanning several plant families and pollinator groups (PGs), and show that the hypothesis of adaptation cannot be rejected: NSP evolves towards two optimal values, high NSP for specialist-pollinated and low NSP for generalist-pollinated plants. However, the inferred adaptive process is weak, suggesting that adaptation to PG only provides a partial explanation for how nectar evolves. Additional factors are therefore needed to fully explain nectar evolution, and we suggest that future studies might incorporate floral shape and size and the abiotic environment into the analytical framework. Further, we show that NSP and PG evolution are correlated - in a manner dictated by pollinator behaviour. This contrasts with the view that a plant necessarily has to adapt its nectar composition to ensure pollination but rather suggests that pollinators adapt their foraging behaviour or dietary requirements to the nectar sugar composition presented by the plants. Finally, we document unexpectedly sucrose-poor nectar in some specialized nectarivorous bird-pollinated plants from the Old World, which might represent an overlooked form of pollinator deception. Thus, our broad study provides several new insights into how nectar evolves and we conclude by discussing why maintaining the conceptual dichotomy between adaptation and constraint might be unhelpful for advancing this field.

Multidisciplinary Management of Phyllodes Tumours and Breast Sarcoma: A Cross-sectional Survey of Clinical Practice across the UK and Ireland.

AIMS: Phyllodes tumours and breast sarcomas are uncommon tumours and their rarity poses significant challenges in diagnosis and management. This cross-sectional study was conducted to evaluate the multidisciplinary clinical practice for these tumours across the UK and Ireland, with the aim of identifying gaps in knowledge and providing direction for establishing national guidelines. MATERIALS AND METHODS: An international survey was adapted and circulated to breast and/or sarcoma surgeons and oncologists in the UK and Ireland through national organisations. Multidisciplinary team (MDT) responses were analysed anonymously. RESULTS: Twenty-eight MDTs participated in this study, predominately from high-volume units (85.5%). Although only 43% of the surveyed units were part of a trust that holds a sarcoma MDT, 68% of units managed malignant phyllodes and angiosarcoma, whereas 64.5% managed soft-tissue sarcoma of the breast. Across all subtypes, axillary surgery was recommended by 14-21% of the MDTs and the most recommended resection margins for breast surgery were 'no tumour on ink' in benign phyllodes (39%) and 10 mm in the remaining subtypes (25-29%). Immediate breast reconstruction was supported by 11-18% of MDTs for breast sarcoma subtypes, whereas 36% and 32% advocated this approach in benign and borderline phyllodes tumours, respectively. Adjuvant radiotherapy and chemotherapy were recommended by up to 29% and 11% of the MDTs, respectively. CONCLUSION: The results of this study demonstrate a wide variation in clinical practice across the surveyed MDTs. As only 28 MDTs participated in our study, with under-representation from low-volume units, our results might be an underestimation of the variability in practice across the UK and Ireland. This multi-institutional study sheds light on controversial aspects in the management of phyllodes tumours and breast sarcoma, identifies the need for national guidelines to inform best practice, and calls for the centralisation of the management of breast sarcoma within specialist centres.

Systematic review and meta-analysis of the retroperitoneal versus the transperitoneal approach to the abdominal aorta.

OBJECTIVES: The aim was to systematically review and meta-analyse the differences between the retroperitoneal (RP) and the transperitoneal (TP) approach to the infrarenal abdominal aorta. DESIGN: Systematic review and meta-analysis. METHODS: PubMed, the Cochrane library, Embase and ClinicalTrials.gov were searched for all studies on differences in clinical outcomes between the RP and TP approach. Outcomes were selected based on inclusion in two or more studies: Operative (length of procedure, intraoperative blood loss); Post operative complications (paralytic ileus, pneumonia, myocardial infarction (MI), renal failure and wound hernia); Mortality (30 day, 1 year); Post-operative changes in respiratory function (forced expiratory volume in 1 second, forced vital capacity); Length of hospital and Intensive care unit (ICU) stay and Cost. The data were pooled by outcome. RESULTS: Eight randomised and 21 cohort studies involving 3035 patients were included. Meta-analysis showed significantly lower rates of postoperative ileus (Odds ratio (OR) 0.17[95% CI 0.10, 0.32] p < 0.00001), pneumonia (OR 0.42[95% CI 0.26, 0.68] p = 0.0004), ICU stay (standardised mean difference (SMD) 0.67[95% CI 1.28, 0.06] p = 0.03), total hospital stay (SMD 0.88[95% CI 1.32, 0.44] p < 0.0001) and cost (SMD 1.15[95% CI 2.11, 0.19] p = 0.02) for patients undergoing a RP approach. Study quality was generally low, with conflicting results and concerns over publication bias in some cohort studies. CONCLUSIONS: The RP approach for open aortic surgery is associated with lower rates of postoperative ileus and pneumonia when compared to the TP approach.

The effect of enzyme supplementation on egg production parameters and omega-3 fatty acid deposition in laying hens fed flaxseed and canola seed.

An experiment was conducted to investigate the effects of a multicarbohydrase enzyme on egg production parameters, nutrient digestibility, and egg fatty acid composition in Hy-Line CV-20 laying hens (39 to 63 wk of age) fed diets containing 150 g/kg of diet of canola seed, flaxseed, or Linpro (flaxseed:peas, 1:1 wt/wt). The diet effect on each parameter was also evaluated. Hens consuming the canola seed and Linpro diets had greater egg production, lower feed consumption, and therefore better feed conversion than those fed the flaxseed diets. Enzyme supplementation significantly increased (P < 0.01) egg production (from 78.0 to 80.9%) and improved (P < 0.001) feed conversion ratio (from 2.15 to 2.03) in hens fed flaxseed. Hens fed the canola seed and Linpro diets produced eggs with greater egg specific gravity than those from birds consuming flaxseed. Enzyme supplementation significantly increased egg specific gravity in hens fed flaxseed (from 1.0773 to 1.0800, P < 0.01) in phase I of the experiment. There was no effect of diet on fat digestibility, and similar fat digestibility values with enzyme supplementation were observed for canola seed (92.1 vs. 96.7%) and flaxseed (87.4 vs. 92.4%). Eggs produced by hens fed flaxseed had the greatest n-3 fatty acid content (562 mg/60 g of egg) when compared with those from hens consuming canola seed (207 mg/60 g of egg) or Linpro (427 mg/60 g of egg). Enzyme supplementation increased the egg n-3 content for the flaxseed diet (from 546 to 578 mg/60 g of egg; P = 0.01) and for the Linpro diet (from 415 to 438 mg/60 g of egg; P = 0.05). In addition, enzyme addition increased the egg docosahexaenoic acid content from 91.8 to 101.9 mg/60 g of egg (P < 0.01) and from 89.4 to 96.8 mg/60 g of egg (P = 0.01) for the flaxseed and Linpro diets, respectively. When compared with canola seed, long-term feeding of flaxseed to laying hens resulted in reduced egg production and eggshell quality. Enzyme supplementation had positive effects on feed utilization, eggshell quality, and n-3 fatty acid deposition in the egg.

Latissimus dorsi myocutaneous reconstruction: a study of long-term outcomes in a district general hospital.

INTRODUCTION The aim of this study was to evaluate the long-term outcome and durability of both autologous and implant-assisted latissimus dorsi reconstruction in a district general hospital over a 10-year follow-up period. METHODS A prospective cohort study was carried out using a detailed database of all latissimus dorsi flap reconstructions performed by a single consultant surgeon between 2003 and 2013 at the Royal United Hospital, Bath. The long-term outcome following reconstruction was assessed by analysing all episodes of 'reconstruction-specific' operations required from 6 months after the initial surgery. RESULTS The study included 110 patients with latissimus dorsi flap reconstructions, 21 autologous and 95 implant-assisted. Radiotherapy was given to 27 patients with reconstructed flaps. Mean follow-up was 69 months. Further reconstruction-specific surgery was needed in 27 (23%) cases, with 5 of these being post-radiotherapy flaps. Implant-related surgery was the most common reason for further surgery. Complications of the implant itself made up 52% of these cases, chronic sepsis being the most common. The rate of symptomatic capsular contracture requiring further surgery was 4.2%. Of these, one of four patients had undergone radiotherapy. DISCUSSION In our institution, latissimus dorsi reconstruction is durable and safe over the long term, with limited need for further substantial intervention to maintain a good outcome from the initial reconstruction. Autologous flaps were less likely to require further surgery over the long term compared with implant-based reconstructions. The low rate of symptomatic capsular contracture may be due to the protective mechanism provided by the extended harvest flap used.

Crystallization and preliminary X-ray analysis of the Fab fragment of a human monoclonal IgM rheumatoid factor (2A2).

Crystals of the Fab fragment of a human monoclonal IgM rheumatoid factor have been obtained and are suitable for X-ray structure determination. This molecule, derived from the synovial B cells of a patient with rheumatoid arthritis, is an autoantibody with specificity for IgG Fc. The crystals have space group P2(1), cell dimensions a = 69.0 A, b = 76.6 A, c = 98.8 A and beta = 90.6 degrees, and diffract to a resolution of at least 2.8 A.

Carboplatin in combination with paclitaxel in advanced ovarian cancer: dose determination and pharmacokinetic and pharmacodynamic interactions.

Data from various phase I/II studies of carboplatin in combination with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have suggested that the degree of thrombocytopenia seen is less than that expected when carboplatin is given alone. However, some studies also have suggested that the area under the plasma concentration-time curve (AUC) of carboplatin is lower than that expected, raising the possibility of a pharmacokinetic interaction. Patients with advanced epithelial ovarian cancer were treated with first-line carboplatin (AUC = 7, using the 51Cr EDTA [edetic acid] clearance method) and escalating doses of paclitaxel. Thrombocytopenia was mild and was significantly less when the paclitaxel dose was 175 mg/m2 versus 150 mg/m2. Paclitaxel kinetics were nonlinear, as previously reported. The achieved carboplatin AUC was 7 +/- 1 mg/mL.min, indicating that the pharmacokinetics of carboplatin are not affected by paclitaxel. Glomerular filtration rates measured in 184 patients using the 51Cr EDTA clearance method were compared with rates estimated from the plasma creatinine level using the Cockcroft-Gault or Jeliffe formulas and showed a significant bias of these two formulas. Clearances above 50 mL/min were underestimated by an amount that became greater as the clearance increased and was approximately 25% to 35% for patients with clearances in the normal range. Since creatinine-based methods have been used in many previous studies, care is needed in interpreting the predicted AUC values from these studies. Carboplatin and paclitaxel may be given safely in combination at full doses, and the thrombocytopenia seen is significantly less than that observed with single-agent carboplatin. No evidence exists of a pharmacokinetic interaction, and the observation in some studies that the carboplatin AUC was lower than expected was probably due to the methodology used to estimate the glomerular filtration rate.

Prognostic value of negative transesophageal dobutamine stress echocardiography in men at high risk for coronary artery disease.

Recently published reviews have called into question the sensitvity of transthoracic stress echocardiography to predict cardiac events, especially when the test is negative, compared with myocardial perfusion imaging studies. To our knowledge there are a lack of data assessing the prognostic value of transesophageal echocardiography-dobutamine stress echocardiography (TEE-DSE) in predicting cardiac events. Because TEE-DSE has been reported to be highly accurate for detecting ischemia in patients with suspected coronary artery disease, we tested the hypothesis that a negative TEE-DSE can identify a low-risk group in a population with a high likelihood of coronary artery disease. Between October 1996 and December 1997, 46 high-risk patients with negative TEE-DSE were identified. Annualized pretest risk for all cardiac events using the Framingham model was 4% based on risk factors. Mean age was 64 years. Mean follow-up time was 16.2 months. There were no cardiac deaths. There were 6 soft and 1 hard cardiac event. The annualized combined ischemic cardiac event rate was 3.8%, and for hard cardiac events it was 1.1%. By Kaplan-Meier analysis, 97% of the population remained free of any ischemic event at the end of 1 year and 93% were free at 22 months. We conclude that optimal image quality and enhanced endocardial definition for assessing wall motion changes with TEE translates into better prognostication and approaches that of myocardial perfusion imaging for negative studies. Advances in ultrasound medicine such as contrast enhancement of myocardial definition, which improve diagnostic accuracy of DSE, should translate into better prognostication.

Monoclonal antibodies against progesterone: effect of steroid-carrier coupling position on antibody specificity.

Monoclonal anti-progesterone antibodies were raised by immunizing mice with progesterone coupled through either the C3, C6 or C11 positions to protein carrier (bovine serum albumin, BSA). The specificity of four antibodies for a range of steroids related to progesterone, some carrying substitutions at various ring positions, was studied by competitive inhibition in an ELISA system. The results demonstrated that the ring coupling position has a determining effect on the cross-reactivity of the antibodies obtained. The patterns of cross-reaction were interpreted in the light of the structure of the combining site of an anti-progesterone antibody (DB3) recently determined by X-ray crystallography, and inferences drawn about the orientation of steroid in the combining sites of the antibodies studied. Specifically, in two antibodies raised against progesterone-11-BSA, the orientation of steroid resembled that of the progesterone-DB3 complex, with positions C11 and C3 exposed and C6 and C20 buried; an antibody raised against progesterone-6-BSA bound steroid in an apparently similar disposition, except that C6 was exposed and C11 buried; finally, in an antibody raised against progesterone-3-BSA, all steroid positions other than C3 were apparently buried in the steroid-antibody complex.

LTP varies across the estrous cycle: enhanced synaptic plasticity in proestrus rats.

Previous studies have shown that the number of dendritic spines and synapses in hippocampal CA1 stratum radiatum decreases more than 30% between the proestrus (high estrogen) and estrus (low estrogen) phases of the rat estrous cycle [10,27]. In the present study, we investigated whether hippocampal synaptic plasticity, as measured by long-term potentiation (LTP), might also vary across the estrous cycle of the female rat. Male rats, and female rats at each phase of the estrous cycle were tested in either the morning or afternoon. There were no significant group differences in the pre-LTP I/O curves. However, females examined during the afternoon of proestrus, the phase during which prior studies indicate synapse number to be highest, demonstrated the greatest degree of potentiation. Diestrus, proestrus and estrus females tested in the morning demonstrated similar amounts of potentiation. There were also significant differences in post-LTP I/O curves between the afternoon proestrus females and males tested in the afternoon. These results suggest that gonadal hormones, interacting with the time of day, may regulate neural processes underlying learning and memory.

Acute dystonic drug reaction or tetanus? An unusual consequence of a 'Whizz' overdose.

The case history presented illustrates that, following an overdose of 'Whizz' and alcohol, a protracted dystonic syndrome can develop, clinically indistinguishable from tetanus. A prolonged period of ventilation may be necessary, but, in this case, complete recovery eventually occurred.

Nurse management of patients with minor illnesses in general practice: multicentre, randomised controlled trial.

OBJECTIVE: To assess the acceptability and safety of a minor illness service led by practice nurses in general practice. DESIGN: Multicentre, randomised controlled trial. SETTING: 5 general practices in south east London and Kent representing semi-rural, suburban, and urban settings. PARTICIPANTS: 1815 patients requesting and offered same day appointments by receptionists. INTERVENTION: Patients were assigned to treatment by either a specially trained nurse or a general practitioner. Patients seen by a nurse were referred to a general practitioner when appropriate. MAIN OUTCOME MEASURES: The general satisfaction of the patients as measured by the consultation satisfaction questionnaire. Other outcome measures included the length of the consultation, number of prescriptions written, rates of referral to general practitioners, patient's reported health status, patient's anticipated behaviour in seeking health care in future, and number of patients who returned to the surgery, visits to accident and emergency, and out of hours calls to doctors. RESULTS: Patients were very satisfied with both nurses and doctors, but they were significantly more satisfied with their consultations with nurses (mean (SD) score of satisfaction 78.6 (16. 0) of 100 points for nurses v 76.4 (17.8) for doctors; 95% confidence interval for difference between means -4.07 to -0.38). Consultations with nurses took about 10 minutes compared with about 8 minutes for consultations with doctors. Nurses and doctors wrote prescriptions for a similar proportion of patients (nurses 481/736 (65.4%) v doctors 518/816 (63.5%)). 577/790 (73%) patients seen by nurses were managed without any input from doctors. CONCLUSION: Practice nurses seem to offer an effective service for patients with minor illnesses who request same day appointments.

The role of the personal tutor in the academic context.

This paper is the second of a series on the role of the nurse teacher and is based on a review of the literature and the personal experience of the authors. Identifying the most appropriate way to support students in both the academic and clinical setting has been a major concern for nurse teachers. The move of nurse education into the higher education arena has increased the diverse nature of the nurse teachers role and raised questions about the nature and function of the personal tutor in relation to students undertaking nursing courses. This paper discusses the concept of the personal tutor, with particular focus on the academic aspects of the role. The time implication of adopting an all encompassing personal tutor role, within the current climate of higher education, is considered. The paper also highlights that the roles tutors adopt in practice are diverse and usually as a result of convenience rather than identified outcomes.

The nature and purpose of the role of the nurse lecturer in practice settings.

This paper examines the role of lecturers in nursing in pre-registration education. It focuses on the nature and purpose of the nurse lecturer's contribution in the practice setting, with particular emphasis on the issues surrounding clinical credibility. This is particularly pertinent in the light of current recommendations, which emphasise the importance of clinical learning in pre-registration education programmes. The purpose of the lecturer's role in clinical practice settings is ill defined. This lack of clear consensus regarding the expected outcomes for lecturers (in practice), leads to difficulty outlining what they should do in practice settings. Although lecturers accept that they have an important part to play in maximizing the learning opportunities for students in both university and practice settings, they are less clear about how this should be achieved in the latter. This paper argues that: It is opportune to examine and realign the lecturers contribution in practice settings given that there has been a shift in the responsibility for clinical learning; nurse education is now embedded in the higher education sector and there is a need for a greater emphasis on practice development. Clinical credibility for lecturers is about the development of nursing practice through education which is not always achieved by 'hands on' care. For example, assisting nurses in a ward area to develop expertise in evidence based practice may not involve 'hands on' care giving but does involve being conversant with current research and practice issues. The lecturer's expertise in practice settings is in teaching and facilitating learning, rather than direct care giving. No one common model for practice may be either feasible or desirable. However, it is important that nurse lecturers do not follow a particular approach because the debate about the nurse lecturer's role in practice settings fails to acknowledge the strengths and weaknesses of each model. It is important that the approach is based on sound rationale.

Effects of personality, perceptual difficulty and pacing of a task on productivity, job satisfaction, and physiological stress.

The relative psychological, physiological, and performance advantages and disadvantages of utilizing machine-paced and self-paced work were examined by having 12 subjects perform a marking-stapling task at 2 levels of perceptual difficulty and under 2 pacing conditions for 30 min. each. (a) 3 subjects who on the personality tests were identified as introverted, reserved, and trusting preferred to work in the machine-paced condition, while 9 subjects who were identified as extroverted, outgoing and suspicious preferred the self-paced condition, (b) the performance errors in machine-paced operation were 372% higher than for self-paced work, and (c) there were no differences between machine-paced and self-paced work on physiological variables, except for sinus arrhythmia for the task with high perceptual load, and quantity of production.

Reflection: does it enhance professional nursing practice?

It is generally accepted that nurses who engage in reflective activity do so to develop their practice. However, there is little empirical evidence to suggest that practice development or improved patient care occurs as a direct result of reflection. The UKCC, as part of its framework for postregistration education, expects all nurses to engage in some form of reflective activity and to provide written accounts within a personal professional profile. This article examines some of the assumptions surrounding the practice of reflection and asserts that, in the main, nurses do not readily engage in reflection in a purposeful way.

Home care for stem cell transplantation patients.

Following high-dose chemotherapy patients need to undergo bone marrow rescue through stem cell transplantation. Patients who received stem cell transplantation at home expressed satisfaction with this form of therapy. Performing stem cell transplantation in the home can reduce both costs and the risk of infection.