Showing papers by "Guy's and St Thomas' NHS Foundation Trust published in 2014"

Enzalutamide in Metastatic Prostate Cancer before Chemotherapy

Abstract: BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS)

Abstract: OBJECTIVE: to examine the clinical evidence reporting the prevalence of sarcopenia and the effect of nutrition and exercise interventions from studies using the consensus definition of sarcopenia proposed by the European Working Group on Sarcopenia in Older People (EWGSOP).METHODS: PubMed and Dialog databases were searched (January 2000-October 2013) using pre-defined search terms. Prevalence studies and intervention studies investigating muscle mass plus strength or function outcome measures using the EWGSOP definition of sarcopenia, in well-defined populations of adults aged ≥50 years were selected.RESULTS: prevalence of sarcopenia was, with regional and age-related variations, 1-29% in community-dwelling populations, 14-33% in long-term care populations and 10% in the only acute hospital-care population examined. Moderate quality evidence suggests that exercise interventions improve muscle strength and physical performance. The results of nutrition interventions are equivocal due to the low number of studies and heterogeneous study design. Essential amino acid (EAA) supplements, including ∼2.5 g of leucine, and β-hydroxy β-methylbutyric acid (HMB) supplements, show some effects in improving muscle mass and function parameters. Protein supplements have not shown consistent benefits on muscle mass and function.CONCLUSION: prevalence of sarcopenia is substantial in most geriatric settings. Well-designed, standardised studies evaluating exercise or nutrition interventions are needed before treatment guidelines can be developed. Physicians should screen for sarcopenia in both community and geriatric settings, with diagnosis based on muscle mass and function. Supervised resistance exercise is recommended for individuals with sarcopenia. EAA (with leucine) and HMB may improve muscle outcomes.

EAACI Food Allergy and Anaphylaxis Guidelines: diagnosis and management of food allergy

Abstract: Food allergy can result in considerable morbidity, impact negatively on quality of life, and prove costly in terms of medical care. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Guidelines for Food Allergy and Anaphylaxis Group, building on previous EAACI position papers on adverse reaction to foods and three recent systematic reviews on the epidemiology, diagnosis, and management of food allergy, and provide evidence-based recommendations for the diagnosis and management of food allergy. While the primary audience is allergists, this document is relevant for all other healthcare professionals, including primary care physicians, and pediatric and adult specialists, dieticians, pharmacists and paramedics. Our current understanding of the manifestations of food allergy, the role of diagnostic tests, and the effective management of patients of all ages with food allergy is presented. The acute management of non-life-threatening reactions is covered in these guidelines, but for guidance on the emergency management of anaphylaxis, readers are referred to the related EAACI Anaphylaxis Guidelines.

Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology

Abstract: A multidisciplinary panel of 18 physicians and 3 nonphysicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.

Epidemiological time series studies of PM2.5 and daily mortality and hospital admissions: a systematic review and meta-analysis

Abstract: Background Short-term exposure to outdoor fine particulate matter (particles with a median aerodynamic diameter 2 . 5 )) air pollution has been associated with adverse health effects. Existing literature reviews have been limited in size and scope. Methods We conducted a comprehensive, systematic review and meta-analysis of 110 peer-reviewed time series studies indexed in medical databases to May 2011 to assess the evidence for associations between PM 2 . 5 and daily mortality and hospital admissions for a range of diseases and ages. We stratified our analyses by geographical region to determine the consistency of the evidence worldwide and investigated small study bias. Results Based upon 23 estimates for all-cause mortality, a 10 µg/m 3 increment in PM 2 . 5 was associated with a 1.04% (95% CI 0.52% to 1.56%) increase in the risk of death. Worldwide, there was substantial regional variation (0.25% to 2.08%). Associations for respiratory causes of death were larger than for cardiovascular causes, 1.51% (1.01% to 2.01%) vs 0.84% (0.41% to 1.28%). Positive associations with mortality for most other causes of death and for cardiovascular and respiratory hospital admissions were also observed. We found evidence for small study bias in single-city mortality studies and in multicity studies of cardiovascular disease. Conclusions The consistency of the evidence for adverse health effects of short-term exposure to PM 2 . 5 across a range of important health outcomes and diseases supports policy measures to control PM 2 . 5 concentrations. However, reasons for heterogeneity in effect estimates in different regions of the world require further investigation. Small study bias should also be considered in assessing and quantifying health risks from PM 2 . 5 .

Thrombosis A Major Contributor to Global Disease Burden

Abstract: Background— Thrombosis is the common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused 1 in 4 deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. Objective— To review the literature on the global burden of disease caused by VTE. Approach and Results— We performed a systematic review of the literature on the global disease burden because of VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1000 individuals in the population. The incidence increased to between 2 and 7 per 1000 among those aged ≥70 years. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted life-years lost in low- and middle-income countries, and second in high-income countries, responsible for more disability-adjusted life-years lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. Conclusions— VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems and to evaluate whether improved use of preventive measures will reduce the burden.

Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG).

Abstract: Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solely on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines.

Thrombosis: a major contributor to global disease burden

Abstract: Thrombosis is a common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused one in four deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. We performed a systematic review of the literature on the global disease burden due to VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1,000 individuals in the population. The incidence increased to between 2 and 7 per 1,000 among those 70 years of age or more. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted-life-years (DALYs) lost in low- and middle-income countries, and second in high-income countries, responsible for more DALYs lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems, and to evaluate if improved utilization of preventive measures will reduce the burden.

EAACI Food Allergy and Anaphylaxis Guidelines. Primary prevention of food allergy

Abstract: Food allergy can have significant effects on morbidity and quality of life and can be costly in terms of medical visits and treatments. There is therefore considerable interest in generating efficient approaches that may reduce the risk of developing food allergy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Prevention and is part of the EAACI Guidelines for Food Allergy and Anaphylaxis. It aims to provide evidence-based recommendations for primary prevention of food allergy. A wide range of antenatal, perinatal, neonatal, and childhood strategies were identified and their effectiveness assessed and synthesized in a systematic review. Based on this evidence, families can be provided with evidence-based advice about preventing food allergy, particularly for infants at high risk for development of allergic disease. The advice for all mothers includes a normal diet without restrictions during pregnancy and lactation. For all infants, exclusive breastfeeding is recommended for at least first 4-6 months of life. If breastfeeding is insufficient or not possible, infants at high-risk can be recommended a hypoallergenic formula with a documented preventive effect for the first 4 months. There is no need to avoid introducing complementary foods beyond 4 months, and currently, the evidence does not justify recommendations about either withholding or encouraging exposure to potentially allergenic foods after 4 months once weaning has commenced, irrespective of atopic heredity. There is no evidence to support the use of prebiotics or probiotics for food allergy prevention.

Anterior cruciate ligament injury and radiologic progression of knee osteoarthritis: a systematic review and meta-analysis.

Abstract: Background:Knee osteoarthritis after anterior cruciate ligament (ACL) injury has previously been reported. However, there has been no meta-analysis reporting the development and progression of osteoarthritis.Purpose:We present the first meta-analysis reporting on the development and progression of osteoarthritis after ACL injury at a minimum mean follow-up of 10 years, using a single and widely accepted radiologic classification, the Kellgren & Lawrence classification.Study Design:Meta-analysis.Method:Articles were included for systematic review if they reported radiologic findings of ACL-injured knees and controls using the Kellgren & Lawrence classification at a minimum mean follow-up period of 10 years. Appropriate studies were then included for meta-analysis.Results:Nine studies were included for systematic review, of which 6 studies were further included for meta-analysis. One hundred twenty-one of 596 (20.3%) ACL-injured knees had moderate or severe radiologic changes (Kellgren & Lawrence grade III ...

Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study

Abstract: To determine the association between compliance with the Surviving Sepsis Campaign (SSC) performance bundles and mortality. Compliance with the SSC performance bundles, which are based on the 2004 SSC guidelines, was measured in 29,470 subjects entered into the SSC database from January 1, 2005 through June 30, 2012. Compliance was defined as evidence that all bundle elements were achieved. Two hundred eighteen community, academic, and tertiary care hospitals in the United States, South America, and Europe. Patients from the emergency department, medical and surgical wards, and ICU who met diagnosis criteria for severe sepsis and septic shock. A multifaceted, collaborative change intervention aimed at facilitating adoption of the SSC resuscitation and management bundles was introduced. Compliance with the SSC bundles and associated mortality rate was the primary outcome variable. Overall lower mortality was observed in high (29.0 %) versus low (38.6 %) resuscitation bundle compliance sites (p < 0.001) and between high (33.4 %) and low (32.3 %) management bundle compliance sites (p = 0.039). Hospital mortality rates dropped 0.7 % per site for every 3 months (quarter) of participation (p < 0.001). Hospital and intensive care unit length of stay decreased 4 % (95 % CI 1–7 %; p = 0.012) for every 10 % increase in site compliance with the resuscitation bundle. This analysis demonstrates that increased compliance with sepsis performance bundles was associated with a 25 % relative risk reduction in mortality rate. Every 10 % increase in compliance and additional quarter of participation in the SSC initiative was associated with a significant decrease in the odds ratio for hospital mortality. These results demonstrate that performance metrics can drive change in clinical behavior, improve quality of care, and may decrease mortality in patients with severe sepsis and septic shock.

Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial

Abstract: Summary Background We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. Methods TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m 2 , 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m 2 orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2–4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. Findings The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4–12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1–8·8] vs 6·9 months [6·4–7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97–1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3–9·7], HR 1·05, 98·25% CI 0·85–1·29, p=0·64; overall log-rank of χ 2 2df =4·3; p=0·11). The commonest grade 3–4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). Interpretation Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. Funding Cancer Research UK and KAEL-GemVax.

Novel techniques for sentinel lymph node biopsy in breast cancer: a systematic review.

Abstract: The existing standard for axillary lymph node staging in breast cancer patients with a clinically and radiologically normal axilla is sentinel lymph node biopsy with a radioisotope and blue dye (dual technique). The dependence on radioisotopes means that uptake of the procedure is limited to only about 60% of eligible patients in developed countries and is negligible elsewhere. We did a systematic review to assess three techniques for sentinel lymph node biopsy that are not radioisotope dependent or that refine the existing method: indocyanine green fluorescence, contrast-enhanced ultrasound using microbubbles, and superparamagnetic iron oxide nanoparticles. Our systematic review suggested that these new methods for sentinel lymph node biopsy have clinical potential but give high levels of false-negative results. We could not identify any technique that challenged the existing standard procedure. Further assessment of these techniques against the standard dual technique in randomised trials is needed.

The impact of pre-operative comprehensive geriatric assessment on postoperative outcomes in older patients undergoing scheduled surgery: a systematic review

Abstract: Comprehensive geriatric assessment is an established clinical approach. It reduces mortality and improves the physical wellbeing of older people in the community or hospitalised for medical reasons. Pre-operative comprehensive geriatric assessment seems a plausible method for reducing adverse postoperative outcomes. The objectives of this systematic review and narrative synthesis are to describe how pre-operative comprehensive geriatric assessment has been used in surgical patients and to examine the impact of comprehensive geriatric assessment on postoperative outcomes in older patients undergoing scheduled surgery. We searched MEDLINE, EMBASE and Web of Science from 1980 to 2013 (week 26). We included five studies: two randomised controlled trials and three before-and-after intervention quasi-experimental studies. Patient populations, interventions and outcome measures varied between studies. Both the randomised trials showed benefit on postoperative outcomes, including medical complications. Two of the before-and-after studies reported a positive impact on postoperative length of stay and other outcomes. The heterogeneity of study methods, populations, interventions and outcomes precluded meta-analysis. Based on this narrative synthesis, pre-operative comprehensive geriatric assessment is likely to have a positive impact on postoperative outcomes in older patients undergoing elective surgery, but further definitive research is required. Clinical services providing pre-operative comprehensive geriatric assessment for older surgical patients should be considered.

Peanut allergy: effect of environmental peanut exposure in children with filaggrin loss-of-function mutations.

Abstract: Background: Filaggrin (FLG) loss-of-function mutations lead to an impaired skin barrier associated with peanut allergy Household peanut consumption is associated with peanut allergy, and peanut allergen in household dust correlates with household peanut consumption Objective: We sought to determine whether environmental peanut exposure increases the odds of peanut allergy and whether FLG mutations modulate these odds Methods: Exposuretopeanutantigenindustwithinthefirstyearof life was measured in a population-based birth cohort Peanut sensitization and peanut allergy (defined by using oral food challengesorcomponent-resolveddiagnostics[CRD])wereassessed at 8 and 11 years Genotyping was performed for 6 FLG mutations Results: After adjustment for infantile atopic dermatitis and preceding egg skin prick test (SPT) sensitization, we found a strong and significant interaction between natural log (ln [loge]) peanutdustlevelsandFLGmutationsonpeanutsensitizationand peanut allergy Among children with FLG mutations, for each ln unit increase in the house dust peanut protein level, there was a morethan6-foldincreasedoddsofpeanutSPTsensitization,CRD sensitization, or both in children at ages 8 years, 11 years, or both and a greater than 3-fold increased odds of peanut allergy compared with odds seen in children with wild-type FLG There was no significant effect of exposure in children without FLG mutations In children carrying an FLG mutation, the threshold level for peanut SPT sensitization was 092 mg of peanut protein per gram (95% CI, 070-122 mg/g), that for CRD sensitization was 103 mg/g (95% CI, 090-182 mg/g), and that for peanut allergy was 117 mg/g (95% CI, 001-16383 mg/g) Conclusion: Early-life environmental peanut exposure is associated with an increased risk of peanut sensitization and allergy in children who carry an FLG mutation These data support the hypothesis that peanut allergy develops throughtranscutaneoussensitizationinchildrenwithanimpaired skin barrier (J Allergy Clin Immunol 2014;134:867-75)

Mutations in TJP2 cause progressive cholestatic liver disease

Abstract: Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.

Factors influencing recruitment to research: qualitative study of the experiences and perceptions of research teams

Abstract: Background Recruiting the required number of participants is vital to the success of clinical research and yet many studies fail to achieve their expected recruitment rate. Increasing research participation is a key agenda within the NHS and elsewhere, but the optimal methods of improving recruitment to clinical research remain elusive. The aim of this study was to identify the factors that researchers perceive as influential in the recruitment of participants to clinically focused research.

Interleukin-17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis.

Abstract: Experimental evidence points to the importance of the cytokine interleukin-17A (IL-17A) in the pathogenesis of several immunoinflammatory diseases including psoriasis, psoriatic arthritis and rheumatoid arthritis. Although a principal effector of T helper type 17 cells, IL-17A is produced by many other cell types including CD8(+) T cells and γδ T cells, and is found at high levels associated with mast cells and neutrophils at sites of skin and joint disease in humans. IL-17A up-regulates expression of numerous inflammation-related genes in target cells such as keratinocytes and fibroblasts, leading to increased production of chemokines, cytokines, antimicrobial peptides and other mediators that contribute to clinical disease features. Importantly, IL-17A must be considered within the context of the local microenvironment, because it acts synergistically or additively with other pro-inflammatory cytokines, including tumour necrosis factor. Several direct IL-17A inhibitors have shown promising activity in proof of concept and phase 2 clinical studies, thereby providing confirmation of experimental data supporting IL-17A in disease pathogenesis, although levels of response are not predicted by pre-clinical findings. IL-17A inhibitors produced rapid down-regulation of the psoriasis gene signature and high clinical response rates in patients with moderate-to-severe plaque psoriasis, consistent with an important role for IL-17A in psoriasis pathogenesis. Clinical response rates with IL-17A inhibitors in psoriatic arthritis and rheumatoid arthritis, however, were improved to a lesser degree compared with placebo, suggesting that IL-17A is either important in a subset of patients or plays a relatively minor role in inflammatory joint disease. Ongoing phase 3 clinical trials should provide further information on the role of IL-17A in these diseases.

Tumor Stage After Neoadjuvant Chemotherapy Determines Survival After Surgery for Adenocarcinoma of the Esophagus and Esophagogastric Junction

Abstract: Purpose Neoadjuvant chemotherapy is established in the management of most resectable esophageal and esophagogastric junction adenocarcinomas. However, assessing the downstaging effects of chemotherapy and predicting response to treatment remain challenging, and the relative importance of tumor stage before and after chemotherapy is debatable. Methods We analyzed consecutive resections for esophageal or esophagogastric junction adenocarcinomas performed at two high-volume cancer centers in London between 2000 and 2010. After standard investigations and multidisciplinary team consensus, all patients were allocated a clinical tumor stage before treatment, which was compared with pathologic stage after surgical resection. Survival analysis was conducted using Kaplan-Meier analysis and Cox regression analysis. Results Among 584 included patients, 400 patients (68%) received neoadjuvant chemotherapy. Patients with downstaged tumors after neoadjuvant chemotherapy experienced improved survival compared with patie...

Impact of centralising acute stroke services in English metropolitan areas on mortality and length of hospital stay: difference-in-differences analysis

Abstract: Objective To investigate whether centralisation of acute stroke services in two metropolitan areas of England was associated with changes in mortality and length of hospital stay. Design Analysis of difference-in-differences between regions with patient level data from the hospital episode statistics database linked to mortality data supplied by the Office for National Statistics. Setting Acute stroke services in Greater Manchester and London, England. Participants 258 915 patients with stroke living in urban areas and admitted to hospital in January 2008 to March 2012. Interventions “Hub and spoke” model for acute stroke care. In London hyperacute care was provided to all patients with stroke. In Greater Manchester hyperacute care was provided to patients presenting within four hours of developing symptoms of stroke. Main outcome measures Mortality from any cause and at any place at 3, 30, and 90 days after hospital admission; length of hospital stay. Results In London there was a significant decline in risk adjusted mortality at 3, 30, and 90 days after admission. At 90 days the absolute reduction was −1.1% (95% confidence interval −2.1 to −0.1; relative reduction 5%), indicating 168 fewer deaths (95% confidence interval 19 to 316) during the 21 month period after reconfiguration in London. In both areas there was a significant decline in risk adjusted length of hospital stay: −2.0 days in Greater Manchester (95% confidence interval −2.8 to −1.2; 9%) and −1.4 days in London (−2.3 to −0.5; 7%). Reductions in mortality and length of hospital stay were largely seen among patients with ischaemic stroke. Conclusions A centralised model of acute stroke care, in which hyperacute care is provided to all patients with stroke across an entire metropolitan area, can reduce mortality and length of hospital stay.

Vitamin B12 deficiency

Abstract: #### Summary points Vitamin B12 is an essential cofactor that is integral to methylation processes important in reactions related to DNA and cell metabolism, thus a deficiency may lead to disruption of DNA and cell metabolism and thus have serious clinical consequences1 Intracellular conversion of vitamin B12 to two active coenzymes, adenosylcobalamin in mitochondria and methylcobalamin in the cytoplasm, is necessary for the homeostasis of methylmalonic acid and homocysteine, respectively2 3 Methylmalonic acid is converted into succinyl-CoA, of which vitamin B12 is a cofactor for the reaction Homocysteine is biosynthesised from methionine then resynthesised into methionine or converted into amino acid cysteine Vitamin B12 (also referred to as cobalamin) deficiency is relatively common, with important and variable clinical consequences This review presents a concise summary of the most up to date evidence on how to diagnose and manage vitamin B12 deficiency #### Sources and selection criteria We searched PubMed and Google Scholar using the terms “vitamin B12 deficiency” and “cobalamin deficiency”, and hand selected the most relevant and appropriate articles We also used evidence based guidelines from the British Committee for Standards in Haematology; however, evidence, especially in the form of randomised controlled trials, is lacking4 Foods containing vitamin B12 are …

Psychological and educational interventions for atopic eczema in children

Abstract: Atopic eczema is an itchy inflammatory skin condition which affects the quality of life of children with eczema and their parents; it can affect up to 15% of school children in the UK. Psychological and educational approaches to treating eczema have been used to complement medication in managing eczema by, for example, promoting relaxation and educating parents and children to understand the condition and their role in its successful management. However, the effectiveness of these approaches has not been systematically reviewed. The main finding of the review is that there is currently only limited research evidence about the effectiveness of educational and psychological approaches when used with medicines for the treatment of childhood eczema. We were only able to include one study on the effectiveness of psychological approaches in the review. We included four educational studies, of which three identified that education decreased the severity of the eczema, and one study found that education improved quality of life for parents of children with eczema. Relaxation methods reduced the severity of the eczema, compared to discussion only, in the psychological study. Two different approaches have been used to deliver education; one led by a nurse and the other by a team of health professionals. Due to weaknesses in the quality of most of the research studies and the fact that different measures were used to evaluate effectiveness of the approaches, we cannot draw strong conclusions about whether psychological and educational approaches work or which is the best approach to use. More details are needed about the psychological and educational approaches used, to allow a greater understanding of the key factors that might help reduce eczema. Better description of the research methods used are also needed. Research priority should also be given to comparing the relative cost effectiveness of health professionals educating parents either in teams or by nurses alone. No adverse effects have been reported. Limitations of the review: We were able to find only five studies eligible for inclusion in the review and we were not able to combine findings from these studies due to the different ways in which effectiveness of the approaches were measured.

Video-assisted thoracoscopic surgery lobectomy at 20 years: A consensus statement

Abstract: OBJECTIVE: Video-assisted thoracoscopic surgery (VATS) lobectomy has been gradually accepted as an alternative surgical approach to open thoracotomy for selected patients with non-small-cell lung cancer (NSCLC) over the past 20 years. The aim of this project was to standardize the perioperative management of VATS lobectomy patients through expert consensus and to provide insightful guidance to clinical practice. METHODS: A panel of 55 experts on VATS lobectomy was identified by the Scientific Secretariat and the International Scientific Committee of the ‘20th Anniversary of VATS Lobectomy Conference—The Consensus Meeting’. The Delphi methodology consisting of two rounds of voting was implemented to facilitate the development of consensus. Results from the second-round voting formed the basis of the current Consensus Statement. Consensus was defined ap riorias more than 50% agreement among the panel of experts. Clinical practice was deemed ‘recommended’ if 50–74% of the experts reached agreement and ‘highly recommended’ if 75% or more of the experts reached agreement. RESULTS: Fifty VATS lobectomy experts (91%) from 16 countries completed both rounds of standardized questionnaires. No statistically significant differences in the responses between the two rounds of questioning were identified. Consensus was reached on 21 controversial points, outlining the current accepted definition of VATS lobectomy, its indications and contraindications, perioperative clinical management and recommendations for training and future research directions. CONCLUSION: The present Consensus Statement represents a collective agreement among 50 international experts to establish a standardized practice of VATS lobectomy for the thoracic surgical community after 20 years of clinical experience.