Thymidylate synthase expression and outcome of patients receiving pemetrexed for advanced nonsquamous non-small-cell lung cancer in a prospective blinded assessment phase II clinical trial

INTRODUCTION In retrospective analyses of patients with nonsquamous non-small-cell lung cancer treated with pemetrexed, low thymidylate synthase (TS) expression is associated with better clinical outcomes. This phase II study explored this association prospectively at the protein and mRNA-expression level. METHODS Treatment-naive patients with nonsquamous non-small-cell lung cancer (stage IIIB/IV) had four cycles of first-line chemotherapy with pemetrexed/cisplatin. Nonprogressing patients continued on pemetrexed maintenance until progression or maximum tolerability. TS expression (nucleus/cytoplasm/total) was assessed in diagnostic tissue samples by immunohistochemistry (IHC; H-scores), and quantitative reverse-transcriptase polymerase chain reaction. Cox regression was used to assess the association between H-scores and progression-free/overall survival (PFS/OS) distribution estimated by the Kaplan-Meier method. Maximal χ analysis identified optimal cutpoints between low TS- and high TS-expression groups, yielding maximal associations with PFS/OS. RESULTS The study enrolled 70 patients; of these 43 (61.4%) started maintenance treatment. In 60 patients with valid H-scores, median (m) PFS was 5.5 (95% confidence interval [CI], 3.9-6.9) months, mOS was 9.6 (95% CI, 7.3-15.7) months. Higher nuclear TS expression was significantly associated with shorter PFS and OS (primary analysis IHC, PFS: p < 0.0001; hazard ratio per 1-unit increase: 1.015; 95%CI, 1.008-1.021). At the optimal cutpoint of nuclear H-score (70), mPFS in the low TS- versus high TS-expression groups was 7.1 (5.7-8.3) versus 2.6 (1.3-4.1) months (p = 0.0015; hazard ratio = 0.28; 95%CI, 0.16-0.52; n = 40/20). Trends were similar for cytoplasm H-scores, quantitative reverse-transcriptase polymerase chain reaction and other clinical endpoints (OS, response, and disease control). CONCLUSIONS The primary endpoint was met; low TS expression was associated with longer PFS. Further randomized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts. © 2013 by the International Association for the Study of Lung Cancer.

Efficacy of a children's procedural preparation and distraction device on healing in acute burn wound care procedures : study protocol for a randomized controlled trial

BACKGROUND: The intense pain and anxiety triggered by burns and their associated wound care procedures are well established in the literature. Non-pharmacological intervention is a critical component of total pain management protocols and is used as an adjunct to pharmacological analgesia. An example is virtual reality, which has been used effectively to dampen pain intensity and unpleasantness. Possible links or causal relationships between pain/anxiety/stress and burn wound healing have previously not been investigated. The purpose of this study is to investigate these relationships, specifically by determining if a newly developed multi-modal procedural preparation and distraction device (Ditto) used during acute burn wound care procedures will reduce the pain and anxiety of a child and increase the rate of re-epithelialization. METHODS/DESIGN: Children (4 to 12 years) with acute burn injuries presenting for their first dressing change will be randomly assigned to either the (1) Control group (standard distraction) or (2) Ditto intervention group (receiving Ditto, procedural preparation and Ditto distraction). It is intended that a minimum of 29 participants will be recruited for each treatment group. Repeated measures of pain intensity, anxiety, stress and healing will be taken at every dressing change until complete wound re-epithelialization. Further data collection will aid in determining patient satisfaction and cost effectiveness of the Ditto intervention, as well as its effect on speed of wound re-epithelialization. DISCUSSION: Results of this study will provide data on whether the disease process can be altered by reducing stress, pain and anxiety in the context of acute burn wounds. TRIAL REGISTRATION: ACTRN12611000913976.

The ENHANCES study--Enhancing Head and Neck Cancer patients' Experiences of Survivorship: study protocol for a randomized controlled trial

Background Few cancers pose greater challenges than head and neck (H&N) cancer. Residual effects following treatment include body image changes, pain, fatigue and difficulties with appetite, swallowing and speech. Depression is a common comorbidity. There is limited evidence about ways to assist patients to achieve optimal adjustment after completion of treatment. In this study, we aim to examine the effectiveness and feasibility of a model of survivorship care to improve the quality of life of patients who have completed treatment for H&N cancer. Methods This is a preliminary study in which 120 patients will be recruited. A prospective randomised controlled trial of the H&N Cancer Survivor Self-management Care Plan (HNCP) involving pre- and post-intervention assessments will be used. Consecutive patients who have completed a defined treatment protocol for H&N cancer will be recruited from two large cancer services and randomly allocated to one of three study arms: (1) usual care, (2) information in the form of a written resource or (3) the HNCP delivered by an oncology nurse who has participated in manual-based training and skill development in patient self-management support. The trained nurses will meet patients in a face-to-face interview lasting up to 60 minutes to develop an individualised HNCP, based on principles of chronic disease self-management. Participants will be assessed at baseline, 3 and 6 months. The primary outcome measure is quality of life. The secondary outcome measures include mood, self-efficacy and health-care utilisation. The feasibility of implementing this intervention in routine clinical care will be assessed through semistructured interviews with participating nurses, managers and administrators. Interviews with patients who received the HNCP will explore their perceptions of the HNCP, including factors that assisted them in achieving behavioural change. Discussion In this study, we aim to improve the quality of life of a patient population with unique needs by means of a tailored self-management care plan developed upon completion of treatment. Delivery of the intervention by trained oncology nurses is likely to be acceptable to patients and, if successful, will be a model of care that can be implemented for diverse patient populations.

Nutritional support in children with end-stage liver disease : a randomized crossover trial of a branched-chain amino acid supplement

Malnutrition is common in children with end-stage liver disease (ESLD) awaiting orthotopic liver transplantation (OLT), and nutritional support is assuming an important role in preoperative management. To evaluate preoperative nutritional therapy, 19 children (median age 1.25 y) with ESLD awaiting OLT were prospectively studied. Two high-energy, isoenergetic and isonitrogenous nutritional formulations delivered nasogastrically were compared: a branched-chain amino acid (BCAA)-enriched semielemental formulation and a matched standard semielemental formulation. Twelve of 19 patients completed a randomized controlled study before OLT and 10 of 19 completed a full crossover study. Improvements in weight and height occurred during the BCAA supplements, with no statistical change on the standard formulation. Significant increases in total body potassium, midupper arm circumference, and subscapular skinfold thickness occurred during the BCAA supplements, whereas no significant changes occurred during the standard formulation period. Significantly fewer albumin infusions were required during the BCAA supplement. These findings suggest that BCAA-enriched formulas have advantages over standard semielemental formulas in improving nutritional status in children with ESLD. and are deserving of wider application and study.

A randomized controlled trial of tea tree oil (5%) body wash versus standard body wash to prevent colonization with methicillin-resistant Staphylococcus aureus (MRSA) in critically ill adults: research protocol

Background
Over the past ten years MRSA has become endemic in hospitals and is associated with increased healthcare costs. Critically ill patients are most at risk, in part because of the number of invasive therapies that they require in the intensive care unit (ICU). Washing with 5% tea tree oil (TTO) has been shown to be effective in removing MRSA on the skin. However, to date, no trials have evaluated the potential of TTO body wash to prevent MRSA colonization or infection. In addition, detecting MRSA by usual culture methods is slow. A faster method using a PCR assay has been developed in the laboratory, but requires evaluation in a large number of patients.

Methods/Design
This study protocol describes the design of a multicentre, phase II/III prospective open-label randomized controlled clinical trial to evaluate whether a concentration of 5% TTO is effective in preventing MRSA colonization in comparison with a standard body wash (Johnsons Baby Softwash) in the ICU. In addition we will evaluate the cost-effectiveness of TTO body wash and assess the effectiveness of the PCR assay in detecting MRSA in critically ill patients. On admission to intensive care, swabs from the nose and groin will be taken to screen for MRSA as per current practice. Patients will be randomly assigned to be washed with the standard body wash or TTO body wash. On discharge from the unit, swabs will be taken again to identify whether there is a difference in MRSA colonization between the two groups.

Discussion
If TTO body wash is found to be effective, widespread implementation of such a simple colonization prevention tool has the potential to impact on patient outcomes, healthcare resource use and patient confidence both nationally and internationally.

Trial Registration
[ISRCTN65190967]

Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa administered monthly:a randomized comparative trial

Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly.

Tea tree oil (5%) body wash versus standard care (Johnson's Baby Softwash) to prevent colonization with methicillin-resistant Staphylococcus aureus in critically ill adults::a randomized controlled trial

OBJECTIVES: To determine whether the daily use of 5% tea tree oil (TTO) body wash (Novabac 5% Skin Wash) compared with standard care [Johnson's Baby Softwash (JBS)] had a lower incidence of methicillin-resistant Staphylococcus aureus (MRSA) colonization.

PATIENTS: The study setting was two intensive care units (ICUs; mixed medical, surgical and trauma) in Northern Ireland between October 2007 and July 2009. The study population comprised 391 patients who were randomized to JBS or TTO body wash.

METHODS: This was a Phase 2/3, prospective, open-label, randomized, controlled trial. Trial registration: ISRCTN65190967. The primary outcome was new MRSA colonization during ICU stay. Secondary outcomes included the incidence of MRSA bacteraemia and maximum increase in sequential organ failure assessment score.

RESULTS: A total of 445 patients were randomized to the study. After randomization, 54 patients were withdrawn; 30 because of a positive MRSA screen at study entry, 11 due to lack of consent, 11 were inappropriately randomized and 2 had adverse reactions. Thirty-nine (10%) patients developed new MRSA colonization (JBS n?=?22, 11.2%; TTO body wash n?=?17, 8.7%). The difference in percentage colonized (2.5%, 95% CI -?8.95 to 3.94; P?=?0.50) was not significant. The mean maximum increase in sequential organ failure assessment score was not significant (JBS 1.44, SD 1.92; TTO body wash 1.28, SD 1.79; P?=?0.85) and no study patients developed MRSA bacteraemia.

CONCLUSIONS: Compared with JBS, TTO body wash cannot be recommended as an effective means of reducing MRSA colonization.

Visual outcomes in the subfoveal radiotherapy study:A randomized controlled trial of teletherapy for age-related macular degeneration

Objective: To determine whether teletherapy with 6-mV photons can reduce visual loss in patients with subfoveal choroidal neovascularization in age-related macular degeneration. Design: A multicenter, single-masked, randomized controlled trial of 12 Gy of external beam radiation therapy delivered to the macula of an affected eye vs observation only. Setting: Three United Kingdom-based hospital units. Participants: Patients with age-related macular degeneration, aged 60 years and older, who had subfoveal choroidal neovascularization and a visual acuity of 20/200 (logMAR 1.0) or better. Methods: Two hundred three patients were randomly assigned to radiotherapy or observation. Treatment was undertaken at designated radiotherapy centers, and patients assigned to the treatment group received a total dosage of 12 Gy of 6-mV photons in 6 fractions. Follow-up was scheduled at 3, 6, 12, and 24 months. After excluding protocol violators, the data from 199 patients were analyzed. Main Outcome Measures: The primary outcome measure was mean loss of distance visual acuity in the study eye at 12 and 24 months. Other outcome variables analyzed were near visual acuity and contrast sensitivity. The proportions of patients losing 3 or more or 6 or more lines of distance and near acuity and 0.3 or more or 0.6 or more log units of contrast sensitivity at each follow-up were also analyzed. Results: At all time points, mean distance visual acuity was better in the radiotherapy-treated group than in the control group, but the differences did not reach statistical significance. At 24 months, analysis of the proportions of patients with loss of 3 or more (moderate) (P=.08) or 6 or more (severe) (P=.29) lines of distance vision showed that fewer treated patients had severe losses, but there was no statistically significant difference between groups. For near visual acuity, although there was no evidence of treatment benefit at 12 and 24 months, a significant difference in favor of treatment was present at 6 months (P=.048). When analyzed by the proportions of patients losing 3 lines of contrast sensitivity, there was a significant difference in favor of treatment at 24 months (P=.02). No adverse retinal effects were observed during the study, but transient disturbance of the precorneal tear film was noted in treated patients. Conclusion: The results of the present trial do not support the routine clinical use of external beam radiation therapy in subjects with subfoveal choroidal neovascularization in age-related macular degeneration.

The United Kingdom Glaucoma Treatment Study:a multicenter, randomized, placebo-controlled clinical trial: design and methodology

Elevated intraocular pressure (IOP) is a major risk factor for the deterioration of open-angle glaucoma (OAG); medical IOP reduction is the standard treatment, yet no randomized placebo-controlled study of medical IOP reduction has been undertaken previously. The United Kingdom Glaucoma Treatment Study (UKGTS) tests the hypothesis that treatment with a topical prostaglandin analog, compared with placebo, reduces the frequency of visual field (VF) deterioration events in OAG patients by 50% over a 2-year period.

Functional multidisciplinary rehabilitation versus outpatient physiotherapy for non specific low back pain: randomized controlled trial.

INTRODUCTION: In recent decades the treatment of non-specific low back pain has turned to active modalities, some of which were based on cognitive-behavioural principles. Non-randomised studies clearly favour functional multidisciplinary rehabilitation over outpatient physiotherapy. However, systematic reviews and meta-analysis provide contradictory evidence regarding the effects on return to work and functional status. The aim of the present randomised study was to compare long-term functional and work status after 3-week functional multidisciplinary rehabilitation or 18 supervised outpatient physiotherapy sessions. METHODS: 109 patients with non-specific low back pain were randomised to either a 3-week functional multidisciplinary rehabilitation programme, including physical and ergonomic training, psychological pain management, back school and information, or 18 sessions of active outpatient physiotherapy over 9 weeks. Primary outcomes were functional disability (Oswestry) and work status. Secondary outcomes were lifting capacity (Spinal Function Sort and PILE test), lumbar range-of-motion (modified-modified Schöber and fingertip-to-floor tests), trunk muscle endurance (Shirado and Biering-Sörensen tests) and aerobic capacity (modified Bruce test). RESULTS: Oswestry disability index was improved to a significantly greater extent after functional multidisciplinary rehabilitation compared to outpatient physiotherapy at follow-up of 9 weeks (P = 0.012), 9 months (P = 0.023) and 12 months (P = 0.011). Work status was significantly improved after functional multidisciplinary rehabilitation only (P = 0.012), resulting in a significant difference compared to outpatient physiotherapy at 12 months' follow-up (P = 0.012). Secondary outcome results were more contrasted. CONCLUSIONS: Functional multidisciplinary rehabilitation was better than outpatient physiotherapy in improving functional and work status. From an economic point of view, these results should be backed up by a cost-effectiveness study.

Flavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studies

Evidence in support of the neuroprotective effects of flavonoids has increased significantly in recent years, although to date much of this evidence has emerged from animal rather than human studies. Nonetheless, with a view to making recommendations for future good practice, we review 15 existing human dietary intervention studies that have examined the effects of particular types of flavonoid on cognitive performance. The studies employed a total of 55 different cognitive tests covering a broad range of cognitive domains. Most studies incorporated at least one measure of executive function/working memory, with nine reporting significant improvements in performance as a function of flavonoid supplementation compared to a control group. However, some domains were overlooked completely (e.g. implicit memory, prospective memory), and for the most part there was little consistency in terms of the particular cognitive tests used making across study comparisons difficult. Furthermore, there was some confusion concerning what aspects of cognitive function particular tests were actually measuring. Overall, while initial results are encouraging, future studies need to pay careful attention when selecting cognitive measures, especially in terms of ensuring that tasks are actually sensitive enough to detect treatment effects.

A multicentre randomized controlled trial of an empowerment-inspired intervention for adolescents starting continuous subcutaneous insulin infusion : a study protocol

Background. Continuous subcutaneous insulin infusion (CSII) treatment among children with type 1 diabetes is increasing in Sweden. However, studies evaluating glycaemic control in children using CSII show inconsistent results. Omitting bolus insulin doses using CSII may cause reduced glycaemic control among adolescents. The distribution of responsibility for diabetes self-management between children and parents is often unclear and needs clarification. There is much published support for continued parental involvement and shared diabetes management during adolescence. Guided Self-Determination (GSD) is an empowerment-based, person-centred, reflection and problem solving method intended to guide the patient to become self-sufficient and develop life skills for managing difficulties in diabetes self-management. This method has been adapted for adolescents and parents as Guided Self-Determination-Young (GSD-Y). This study aims to evaluate the effect of an intervention with GSD-Y in groups of adolescents starting on insulin pumps and their parents on diabetes-related family conflicts, perceived health and quality of life (QoL), and metabolic control. Here, we describe the protocol and plans for study enrolment. Methods. This study is designed as a randomized, controlled, prospective, multicentre study. Eighty patients between 12-18 years of age who are planning to start CSII will be included. All adolescents and their parents will receive standard insulin pump training. The education intervention will be conducted when CSII is to be started and at four appointments in the first 4 months after starting CSII. The primary outcome is haemoglobin A1c levels. Secondary outcomes are perceived health and QoL, frequency of blood glucose self-monitoring and bolus doses, and usage of carbohydrate counting. The following instruments will be used to evaluate perceived health and QoL: Disabkids, 'Check your health', the Diabetes Family Conflict Scale and the Swedish Diabetes Empowerment Scale. Outcomes will be evaluated within and between groups by comparing data at baseline, and at 6 and 12 months after starting treatment. Results and discussion. In this study, we will assess the effect of starting an insulin pump together with the model of Guided Self-Determination to determine whether this approach leads to retention of improved glycaemic control, QoL, responsibility distribution and reduced diabetes-related conflicts in the family. Trial registration: Current controlled trials: ISRCTN22444034

Effectiveness and safety of endotracheal tube cuffs filled with air versus filled with alkalinized lidocaine: a randomized clinical trial

CONTEXTO E OBJETIVO: Os tubos traqueais são dispositivos utilizados para manutenção da ventilação. A hiperinsuflação do balonete do tubo traqueal, causada pela difusão do óxido nitroso (N2O), pode determinar lesões traqueais, que se manifestam clinicamente como odinofagia, rouquidão e tosse. A lidocaína, quando injetada no balonete do tubo traqueal, difunde-se através de sua parede, determinando ação anestésica local na traquéia. O objetivo foi avaliar a efetividade e a segurança do balonete do tubo traqueal preenchido com ar comparado com o balonete preenchido com lidocaína, considerando os desfechos: sintomas cardiovasculatórios (HAS, taquicardia); odinofagia, tosse, rouquidão e tolerância ao tubo traqueal. TIPO DE ESTUDO E LOCAL: Estudo clínico prospectivo, realizado no Departamento de Anestesiologia da Faculdade de Medicina da Unesp, campus de Botucatu. MÉTODOS: A pressão do balonete do tubo traqueal foi medida, entre 50 pacientes, antes, 30, 60, 90 e 120 minutos após o início da inalação de N2O anestésico. As pacientes foram distribuídas aleatoriamente em dois grupos: Air, em que o balonete foi inflado com ar para obtenção de pressão de 20 cm H2O, e Lido, em que o balonete foi preenchido com lidocaína a 2% mais bicarbonato de sódio a 8,4% para obtenção da mesma pressão. O desconforto antes da extubação, e manifestações clínicas como dor de garganta, rouquidão e tosse foram registrados no momento da alta da unidade de cuidados pós-anestésicos, e dor de garganta e rouquidão foram avaliadas também 24 horas após a anestesia. RESULTADOS: Os valores da pressão no balonete em G2 foram significativamente menores do que os de Air em todos os tempos de estudo, a partir de 30 minutos (p < 0,001). A proporção de pacientes que reagiu ao tubo traqueal no momento da desintubação foi significantemente menor em Lido (p < 0,005). A incidência de odinofagia foi significantemente menor em Lido no primeiro dia de pós-operatório (p < 0,05). A incidência de tosse e rouquidão não diferiu entre os grupos. CONCLUSÕES: Durante ventilação artificial, empregando-se a mistura de oxigênio e N2O, a insuflação do balonete com lidocaína 2% alcalinizada impede que ocorra aumento significante da pressão no balonete e determina maior tolerância ao tubo traqueal e menor incidência de odinofagia no pós-operatório, podendo então ser considerada mais segura e com maior efetividade.

Labor analgesia with ropivacaine added to clonidine: a randomized clinical trial

CONTEXTO E OBJETIVO: A associação entre ropivacaína e clonidina agiria menos que a ropivacaína isolada na mãe e no feto? Foram pesquisados os efeitos materno-fetais de duas técnicas farmacológicas: pequena dose de ropivacaína ou dose menor de ropivacaína mais clonidina na analgesia peridural para parto. TIPO DE ESTUDO E LOCAL: Estudo prospectivo, Departamento de Anestesiologia, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista. MÉTODOS: Trinta e duas parturientes, estado físico de acordo com a American Society of Anesthesiologists I e II, foram aleatoriamente submetidas à analgesia peridural com 15 ml de ropivacaína 0,125% (grupo R) ou 15 ml de ropivacaína 0,0625% mais clonidina, 75 µg (grupo RC). Foram avaliados: intensidade da dor, nível do bloqueio sensitivo, latência, intensidade do bloqueio motor, duração da analgesia de parto e da analgesia peridural. Os neonatos foram avaliados pelo Apgar e método de Amiel-Tison (capacidade neurológica e adaptativa). RESULTADOS: Não houve diferenças significativas entre grupos para dor, nível de bloqueio sensitivo, duração da analgesia peridural e Apgar. Para latência, duração da analgesia de parto e bloqueio motor, grupo R < grupo RC. O escore da capacidade neurológica e adaptativa de meia e duas horas foi maior para o grupo R. Cem por cento dos neonatos do grupo R e 75% dos do grupo RC estavam neurologicamente saudáveis ao exame de 24 horas. CONCLUSÃO: Pequena dose de ropivacaína e dose menor mais clonidina aliviaram a dor materna durante o parto. Neonatos de mães que receberam apenas ropivacaína mostraram melhores escores da capacidade neurológica e adaptativa.