TRAFIC: statistical design and analysis plan for a pragmatic early phase 1/2 Bayesian adaptive dose escalation trial in rheumatoid arthritis.

BACKGROUND: Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity but uptake has been slow especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in rheumatoid arthritis incorporating a model-based design. METHODS: A Bayesian adaptive dose-finding phase I trial rolling into a single-arm, single-stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways. DISCUSSION: TRAFIC is an MRC-funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. The phase I design allows borrowing of information from previous trials, all accumulated data to be utilised in decision-making, verification of operating characteristics through simulation, improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities and cost. TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation. TRIAL REGISTRATION: Trials Registration: ISRCTN, ISRCTN36667085 . Registered on September 26, 2014.

Folic acid supplementation in postmenopausal women with hot flushes: phase III randomised double-blind placebo-controlled trial.

OBJECTIVE: To assess whether folic acid supplementation ameliorates hot flushes. DESIGN: Double-blind, placebo-controlled randomised trial. SETTING: Nine hospitals in England. POPULATION: Postmenopausal women experiencing ≥50 hot flushes weekly. METHODS: Women (n = 164) were randomly assigned in a 1:1 ratio to receive folic acid 5 mg tablet or placebo daily for 12 weeks. Participants recorded frequency and severity of hot flushes in a Sloan Diary daily and completed Greene Climacteric and Utian Quality of Life (UQoL) Scales at 4-week intervals. MAIN OUTCOME MEASURES: The change in daily Hot Flush Score at week 12 from randomisation based on Sloan Diary Composite Score B calculation. RESULTS: Data of 143 (87%) women were available for the primary outcome. The mean change (SD) in Hot Flush Score at week 12 was -6.98 (10.30) and -4.57 (9.46) for folic acid and placebo group, respectively. The difference between groups in the mean change was -2.41 (95% CI -5.68 to 0.87) (P = 0.149) and in the adjusted mean change -2.61 (95% CI -5.72 to 0.49) (P = 0.098). Analysis of secondary outcomes indicated an increased benefit in the folic acid group regarding changes in total and emotional UQoL scores at week 8 when compared with placebo. The difference in the mean change from baseline was 5.22 (95% CI 1.16-9.28) and 1.88 (95% CI 0.23-3.52) for total and emotional score, respectively. CONCLUSIONS: The study was not able to demonstrate that folic acid had a statistically significant greater benefit in reducing Hot Flush Score over 12 weeks in postmenopausal women when compared with placebo. TWEETABLE ABSTRACT: Folic acid may ameliorate hot flushes in postmenopausal women but confirmation is required from a larger study.

Defining trajectories of response in patients with psoriasis treated with biologic therapies.

BACKGROUND: The effectiveness and cost-effectiveness of biologic therapies for psoriasis are significantly compromised by variable treatment responses. Thus, more precise management of psoriasis is needed. OBJECTIVES: To identify subgroups of patients with psoriasis treated with biologic therapies, based on changes in their disease activity over time, that may better inform patient management. METHODS: We applied latent class mixed modelling to identify trajectory-based patient subgroups from longitudinal, routine clinical data on disease severity, as measured by the Psoriasis Area and Severity Index (PASI), from 3546 patients in the British Association of Dermatologists Biologics and Immunomodulators Register, as well as in an independent cohort of 2889 patients pooled across four clinical trials. RESULTS: We discovered four discrete classes of global response trajectories, each characterized in terms of time to response, size of effect and relapse. Each class was associated with differing clinical characteristics, e.g. body mass index, baseline PASI and prevalence of different manifestations. The results were verified in a second cohort of clinical trial participants, where similar trajectories following the initiation of biologic therapy were identified. Further, we found differential associations of the genetic marker HLA-C*06:02 between our registry-identified trajectories. CONCLUSIONS: These subgroups, defined by change in disease over time, may be indicative of distinct endotypes driven by different biological mechanisms and may help inform the management of patients with psoriasis. Future work will aim to further delineate these mechanisms by extensively characterizing the subgroups with additional molecular and pharmacological data.

Laparoscopic versus open colorectal surgery in the acute setting (LaCeS trial): a multicentre randomized feasibility trial.

BACKGROUND: Approximately 30 000 people undergo major emergency abdominal gastrointestinal surgery annually, and 36 per cent of these procedures (around 10 800) are carried out for emergency colorectal pathology. Some 14 per cent of all patients requiring emergency surgery have a laparoscopic procedure. The aims of the LaCeS (laparoscopic versus open colorectal surgery in the acute setting) feasibility trial were to assess the feasibility, safety and acceptability of performing a large-scale definitive phase III RCT, with a comparison of emergency laparoscopic versus open surgery for acute colorectal pathology. METHODS: LaCeS was designed as a prospective, multicentre, single-blind, parallel-group, pragmatic feasibility RCT with an integrated qualitative study. Randomization was undertaken centrally, with patients randomized on a 1 : 1 basis between laparoscopic or open surgery. RESULTS: A total of 64 patients were recruited across five centres. The overall mean steady-state recruitment rate was 1·2 patients per month per site. Baseline compliance for clinical and health-related quality-of-life data was 99·8 and 93·8 per cent respectively. The conversion rate from laparoscopic to open surgery was 39 (95 per cent c.i. 23 to 58) per cent. The 30-day postoperative complication rate was 27 (13 to 46) per cent in the laparoscopic arm and 42 (25 to 61) per cent in the open arm. CONCLUSION: Laparoscopic emergency colorectal surgery may have an acceptable safety profile. Registration number: ISRCTN15681041 ( http://www.controlled-trials.com).

ANTECEDENTES: Aproximadamente 30.000 personas se someten cada año una operación de cirugía mayor urgente gastrointestinal de las cuales el 36% (~ 10.800) se realizan por patología colorrectal urgente. Aproximadamente el 14% de todos los pacientes que requieren cirugía urgente son operados mediante abordaje laparoscópico. Los objetivos del ensayo de factibilidad LaCeS (Laparoscopic versus Open Colorectal Surgery in the Acute Setting; Cirugía Colorrectal Laparoscópica versus Abierta en Urgencias) fueron evaluar la factibilidad, seguridad y aceptabilidad de realizar un ensayo clínico aleatorizado definitivo a gran escala de fase III comparando la cirugía colorrectal urgente por vía laparoscópica con el abordaje abierto. MÉTODOS: LaCeS se diseñó como un ensayo clínico prospectivo, multicéntrico, simple ciego, de grupos paralelos, pragmático, aleatorizado (factibilidad) con un estudio cualitativo integrado. La asignación al azar se realizó de forma centralizada y los pacientes se asignaron al azar en proporción 1:1 a cirugía laparoscópica o abierta. RESULTADOS: Un total de 64 pacientes fueron reclutados en 5 centros. La tasa media global estable de reclutamiento fue de 1,2 pacientes/mes. El cumplimiento inicial de los datos clínicos y de calidad de vida (HRQoL) fue del 99,8% y del 93,8%, respectivamente. La tasa de conversión de la cirugía laparoscópica a cirugía abierta fue del 39,4% (i.c. del 95%: 22,9% a 57,9%). La tasa de complicaciones postoperatorias a los 30 días fue del 27,3% (i.c. del 95%: 13,3-45,5) para la cirugía laparoscópica y del 41,9% (i.c. del 95%: 24,6-60,9) para la cirugía abierta. CONCLUSIÓN: La cirugía colorrectal urgente por vía laparoscópica puede tener un perfil de seguridad aceptable.

Psoriasis treat to target: defining outcomes in psoriasis using data from a real-world, population-based cohort study (the British Association of Dermatologists Biologics and Immunomodulators Register, BADBIR).

BACKGROUND: The 'treat to target' paradigm improves outcomes and reduces costs in chronic disease management but is not yet established in psoriasis. OBJECTIVES: To identify treatment targets in psoriasis using two common measures of disease activity: Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). METHODS: Data from a multicentre longitudinal U.K. cohort of patients with psoriasis receiving systemic or biologic therapies (British Association of Dermatologists Biologics and Immunomodulators Register, BADBIR) were used to identify absolute PASI thresholds for 90% (PASI 90) and 75% (PASI 75) improvements in baseline disease activity, using receiver operating characteristic curves. The relationship between PGA (clear, almost clear, mild, moderate, moderate-severe, severe) and PASI (range 0-72) was described, and the concordance between absolute and relative definitions of response was determined. The same approach was used to establish treatment response and eligibility definitions based on PGA. RESULTS: Data from 13 422 patients were available (58% male, 91% white ethnicity, mean age 44·9 years), including over 23 000 longitudinal PASI and PGA scores. An absolute PASI ≤ 2 was concordant with PASI 90 and an absolute PASI ≤ 4 was concordant with PASI 75 in 90% and 88% of cases, respectively. These findings were robust to subgroups of timing of assessment, baseline disease severity and treatment modality. PASI and PGA were strongly correlated (Spearman's rank correlation coefficient 0·92). The median PASI increased from 0 (interquartile range 0-0, range 0-23) to 19 (interquartile range 15-25, range 0-64) for PGA clear to severe, respectively. PGA clear/almost clear was concordant with PASI ≤ 2 in 90% of cases, and PGA moderate-severe severe was concordant with the National Institute for Health and Care Excellence PASI eligibility criteria for biologics in 81% of cases. CONCLUSIONS: An absolute PASI ≤ 2 and PGA clear/almost clear represent relevant disease end points to inform treat-to-target management strategies in psoriasis. What's already known about this topic? The most commonly used relative disease activity measure in psoriasis is ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90); however, it has several limitations including dependency on a baseline severity assessment. Defining an absolute target disease activity end point in psoriasis has the potential to improve patient outcomes and reduce costs, as demonstrated by treat-to-target approaches in other chronic diseases such as hypertension and diabetes. The Physician's Global Assessment (PGA) is a popular alternative measure of psoriasis severity in daily practice; however, its utility has not been formally assessed with respect to PASI. What does this study add? An absolute PASI ≤ 2 corresponds with PASI 90 response and is a relevant disease end point for treat-to-target approaches in psoriasis. There is a strong correlation between PASI and PGA. PGA moderate-severe/severe may serve as an alternative eligibility criterion for biologics to PASI-based definitions, and PGA clear/almost clear is an appropriate alternative absolute treatment end point. What are the clinical implications of this work? Absolute PASI ≤ 2 and PGA clear/almost clear represent relevant disease end points to inform treat-to-target management strategies in psoriasis.

Meta-analysis of fenestrated endovascular aneurysm repair versus open surgical repair of juxtarenal abdominal aortic aneurysms over the last 10 years.

Background: Juxtarenal abdominal aortic aneurysms pose a significant challenge whether managed endovascularly or by open surgery. Fenestrated endovascular aneurysm repair (FEVAR) is now well established, but few studies have compared it with open surgical repair (OSR). The aim of this systematic review was to compare short- and long-term outcomes of FEVAR and OSR for the management of juxtarenal aortic aneurysms. Methods: A literature search was conducted of the Ovid Medline, EMBASE and PubMed databases. Reasons for exclusion were series with fewer than 20 patients, studies published before 2007 and those concerning ruptured aneurysms. Owing to variance in definitions, the terms 'juxta/para/suprarenal' were used; thoracoabdominal aortic aneurysms were excluded. Primary outcomes were 30-day/in-hospital mortality and renal insufficiency. Secondary outcomes included major complication rates, rate of reintervention and rates of endoleak. Results: Twenty-seven studies were identified, involving 2974 patients. Study designs included 11 case series, 14 series within retrospective cohort studies, one case-control study and a single prospective non-randomized trial. The pooled early postoperative mortality rate following FEVAR was 3·3 (95 per cent c.i. 2·0 to 5·0) per cent, compared with 4·2 (2·9 to 5·7) per cent after OSR. After FEVAR, the rate of postoperative renal insufficiency was 16·2 (10·4 to 23·0) per cent, compared with 23·8 (15·2 to 33·6) per cent after OSR. The major early complication rate following FEVAR was 23·1 (16·8 to 30·1) per cent versus 43·5 (34·4 to 52·8) per cent after OSR. The rate of late reintervention after FEVAR was higher than that after OSR: 11·1 (6·7 to 16·4) versus 2·0 (0·6 to 4·3) per cent respectively. Conclusion: No significant difference was noted in 30-day mortality; however, FEVAR was associated with significantly lower morbidity than OSR. Long-term durability is a concern, with far higher reintervention rates after FEVAR.

Antecedentes: Los aneurismas de la aorta abdominal yuxtarrenal plantean un gran reto sobre si tratarlos de forma endovascular o mediante cirugía abierta. La reparación del aneurisma con endoprótesis fenestrada (fenestrated endovascular aneurysm repair, FEVAR) no esta consolidada, sin embargo, algunos pocos estudios, la comparan con la reparación quirúrgica por vía abierta (open surgical repair, OSR). El objetivo de esta revisión sistemática fue comparar los resultados a corto y largo plazo de FEVAR y OSR para el tratamiento de los aneurismas aórticos yuxtarrenales. Métodos: Se llevó a cabo una búsqueda de la literatura en las bases de datos Ovid Medline, EMBASE y Pubmed. Las razones para exclusión fueron series con menos de 20 pacientes, aquellas publicadas antes de 2007 y los trabajos sobre aneurismas rotos. Debido a las diferencias en las definiciones, se utilizaron los términos "yuxta/para/suprarrenal"; se excluyeron los aneurismas de la aorta tóracoabdominal. Los resultados primarios fueron la mortalidad a 30 días/intrahospitalaria y la insuficiencia renal. Los resultados secundarios incluyeron las tasas de complicaciones mayores, tasa de reintervención y tasas de fugas internas. Resultados: Se identificaron un total de 27 estudios, que incluían 2.974 pacientes. Los diseños de los estudios incluían 11 series de casos, 12 estudios de cohortes retrospectivos, un estudio caso­control y un único ensayo no aleatorizado prospectivo. La mortalidad postoperatoria precoz agrupada tras FEVAR fue del 3,3% (i.c. del 95% 2,0­5,0), comparado con el 4,2% (i.c. del 95% 2,9­5,7) tras OSR. Después de FEVAR, la tasa de insuficiencia renal postoperatoria fue del 16,2% (i.c. del 95% 10,4­23,0) comparada con el 23,8% (i.c. del 95% 15,2­33,6) después de OSR. La tasa de complicaciones mayores precoces tras FEVAR fue del 23,1% (i.c. del 95% 16,8­30,1) comparada con el 43,5% (i.c. del 95% 34,4­52,8) después de OSR. La tasa de reintervención tardía tras FEVAR fue superior que tras OSR: 11,1% (i.c. del 95% 6,7­16,4) y 2,0% (i.c. del 95% 0,6­4,3), respectivamente. Conclusión: No se observaron diferencias significativas en la mortalidad a los 30 días, sin embargo, FEVAR presentó una morbilidad significativamente menor que OSR. La durabilidad a largo plazo es una preocupación con muchas mayores tasas de reintervención después de FEVAR.

Identifying demographic, social and clinical predictors of biologic therapy effectiveness in psoriasis: a multicentre longitudinal cohort study.

BACKGROUND: Biologic therapies have revolutionized the treatment of moderate-to-severe psoriasis. However, for reasons largely unknown, many patients do not respond or lose response to these drugs. OBJECTIVES: To evaluate demographic, social and clinical factors that could be used to predict effectiveness and stratify response to biologic therapies in psoriasis. METHODS: Using a multicentre, observational, prospective pharmacovigilance study (BADBIR), we identified biologic-naive patients starting biologics with outcome data at 6 (n = 3079) and 12 (n = 3110) months. Associations between 31 putative predictors and outcomes were investigated in univariate and multivariable regression analyses. Potential stratifiers of treatment response were investigated with statistical interactions. RESULTS: Eight factors associated with reduced odds of achieving ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) at 6 months were identified (described as odds ratio and 95% confidence interval): demographic (female sex, 0·78, 0·66-0·93); social (unemployment, 0·67, 0·45-0·99); unemployment due to ill health (0·62, 0·48-0·82); ex- and current smoking (0·81, 0·66-0·99 and 0·79, 0·63-0·99, respectively); clinical factors (high weight, 0·99, 0·99-0·99); psoriasis of the palms and/or soles (0·75, 0·61-0·91); and presence of small plaques only compared with small and large plaques (0·78, 0·62-0·96). White ethnicity (1·48, 1·12-1·97) and higher baseline PASI (1·04, 1·03-1·04) were associated with increased odds of achieving PASI 90. The findings were largely consistent at 12 months. There was little evidence for predictors of differential treatment response. CONCLUSIONS: Psoriasis phenotype and potentially modifiable factors are associated with poor outcomes with biologics, underscoring the need for lifestyle management. Effect sizes suggest that these factors alone cannot inform treatment selection.

Systematic review of endovascular intervention and surgery for common femoral artery atherosclerotic disease.

BACKGROUND: Endovascular intervention has emerged as a potential alternative to open surgery in treating common femoral artery (CFA) atherosclerotic disease. The aim of this systematic review was to assess the safety and efficacy of both techniques. METHODS: Thirteen electronic databases from 1980 to 3 January 2018 were searched. Study quality was assessed using the National Institute for Health and Care Excellence Interventional Procedure Programme quality assessment tool. Safety and efficacy outcome measures were analysed. RESULTS: Thirty-one studies reporting 813 endovascular procedures and 3835 endarterectomies were included. Only two small RCTs have been reported. The methodological quality of available studies was generally low and follow-up short. Safety endpoint assessment revealed a similar risk of wound haematoma for endovascular intervention and endarterectomy (5·5 (95 per cent c.i. 0·2 to 17·2) versus 3·9 (1·7 to 6·9) per cent respectively), a lower risk of wound infection with endovascular procedures (0 versus 5·9 (3·4 to 9·0) per cent) and a lower risk of wound lymph leakage (0 versus 5·7 (3·3 to 8·6) per cent). Efficacy endpoint assessment at 1 year identified that endovascular intervention had a lower primary patency rate than endarterectomy (78·8 (73·3 to 83·8) versus 96·0 (92·2 to 98·6) per cent respectively), a higher revascularization rate (16·0 (6·1 to 29·4) versus 5·8 (1·0 to 14·2) per cent) and a similar amputation rate (2·7 (1·2 to 4·8) versus 1·9 (0·7 to 3·8) per cent). CONCLUSION: Endovascular intervention of CFA disease appears to reduce the risk of wound complications but is associated with a lower patency rate and increased rates of subsequent revascularization procedures. Standardization of the endovascular technique and quantification of the proportions of patients suitable for either technique are required.

An observer-blinded randomized controlled pilot trial comparing localized immersion psoralen-ultraviolet A with localized narrowband ultraviolet B for the treatment of palmar hand eczema.

BACKGROUND: Hand eczema is a common inflammatory dermatosis that causes significant patient morbidity. Previous studies comparing psoralen-ultraviolet A (PUVA) with narrowband ultraviolet B (NB-UVB) have been small, nonrandomized and retrospective. OBJECTIVES: To conduct an observer-blinded randomized controlled pilot study using validated scoring criteria to compare immersion PUVA with NB-UVB for the treatment of chronic hand eczema unresponsive to topical steroids. METHODS: Sixty patients with hand eczema unresponsive to clobetasol propionate 0·05% were randomized to receive either immersion PUVA or NB-UVB twice weekly for 12 weeks with assessments at intervals of 4 weeks. The primary outcome measure was the proportion of patients achieving 'clear' or 'almost clear' Physician's Global Assessment (PGA) response at 12 weeks. Secondary outcome measures included assessment of the modified Total Lesion and Symptom Score (mTLSS) and the Dermatology Life Quality index (DLQI). RESULTS: In both treatment arms, 23 patients completed the 12-week assessment for the primary outcome measure. In the PUVA group, five patients achieved 'clear' and eight 'almost clear' [intention-to-treat (ITT) response rate 43%]. In the NB-UVB group, two achieved 'clear' and five 'almost clear' (ITT response rate 23%). For the secondary outcomes, median mTLSS scores were similar between groups at baseline (PUVA 9·5, NB-UVB 9) and at 12 weeks (PUVA 3, NB-UVB 4). Changes in DLQI were similar, with improvements in both groups. CONCLUSIONS: In this randomized pilot trial recruitment was challenging. After randomization, there were acceptable levels of compliance and safety in each treatment schedule, but lower levels of retention. Using validated scoring systems - PGA, mTLSS and DLQI - as measures of treatment response, the trial demonstrated that both PUVA and NB-UVB reduced the severity of chronic palmar hand eczema.

'Thinking that somebody's going to delay [a tonsillectomy] for one to two years is quite horrifying really': a qualitative feasibility study for the NAtional Trial of Tonsillectomy IN Adults (NATTINA Part 2).

OBJECTIVES: Level one evidence on the value of adult tonsillectomy versus non-surgical management remains scarce. Before embarking on a costly national randomised controlled trial, it is essential to establish its feasibility. DESIGN: Feasibility study with in-depth qualitative and cognitive interviews. SETTING: ENT staff and patients were recruited from nine hospital centres across England and Scotland. PARTICIPANTS: Patients who were referred for tonsillectomy (n = 15), a convenience sample of general practitioners (n = 11) and ear, nose and throat staff (n = 22). MAIN OUTCOME MEASURES: To ascertain whether ear, nose and throat staff would be willing to randomise patients to the treatment arms. To assess general practitioners' willingness to refer patients to the NAtional Trial of Tonsillectomy IN Adults (NATTINA) centres. To assess patients' willingness to be randomised and the acceptability of the deferred surgery treatment arm. To ascertain whether the study could progress to the pilot trial stage. RESULTS: Ear, nose and throat staff and general practitioners were willing to randomise patients to the proposed NATTINA. Not all ENT staff were in equipoise concerning the treatment pathways. Patients were reluctant to be randomised into the deferred surgery group if they had already waited a substantial time before being referred. CONCLUSIONS: Findings suggest that the NATTINA may not be feasible. Proposed methods could not be realistically assessed without a pilot trial. Due to the importance of the question, as evidenced by NATTINA clinicians, and strong support from ENT staff, the pilot trial proceeded, with modifications.

The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis.

BACKGROUND: Age at presentation with primary biliary cholangitis (PBC) is associated with differential response to ursodeoxycholic acid (UDCA) therapy. Younger-presenting patients are less likely to respond to treatment and more likely to need transplant or die from the disease. PBC has a complex impact on quality of life (QoL), with systemic symptoms often having significant impact. AIM: To explain the impact of age at presentation on perceived QoL and the inter-related symptoms which impact upon it. METHODS: Using the UK-PBC cohort, symptoms were assessed using the PBC-40 and other validated tools. Data were available on 2055 patients. RESULTS: Of the 1990 patients reporting a global PBC-QoL score, 66% reported good/neutral scores and 34% reported poor scores. Each 10-year increase in age at presentation was associated with a 14% decrease in risk of poor perceived QoL (OR = 0.86, 95% CI: 0.75-0.98, P < 0.05). All symptom domains were similarly age-associated (P < 0.01). Social dysfunction was the symptom factor with the greatest impact on QoL. Median (interquartile range) PBC-40 social scores for patients with good perceived QoL were 18 (14-23) compared with 34 (29-39) for those with poor QoL. CONCLUSION: The majority of patients with primary biliary cholangitis do not feel their QoL is impaired, although impairment is reported by a sizeable minority. Age at presentation is associated with impact on perceived QoL and the symptoms impairing it, with younger patients being more affected. Social dysfunction makes the greatest contribution to QoL impairment, and it should be targeted in trials aimed at improving life quality.

REpeated AutoLogous Infusions of STem cells In Cirrhosis (REALISTIC): a multicentre, phase II, open-label, randomised controlled trial of repeated autologous infusions of granulocyte colony-stimulating factor (GCSF) mobilised CD133+ bone marrow stem cells in patients with cirrhosis. A study protocol for a randomised controlled trial.

INTRODUCTION: Liver disease mortality and morbidity are rapidly rising and liver transplantation is limited by organ availability. Small scale human studies have shown that stem cell therapy is safe and feasible and has suggested clinical benefit. No published studies have yet examined the effect of stem cell therapy in a randomised controlled trial and evaluated the effect of repeated therapy. METHODS AND ANALYSIS: Patients with liver cirrhosis will be randomised to one of three trial groups: group 1: Control group, Standard conservative management; group 2 treatment: granulocyte colony-stimulating factor (G-CSF; lenograstim) 15 µg/kg body weight daily on days 1-5; group 3 treatment: G-CSF 15 µg/kg body weight daily on days 1-5 followed by leukapheresis, isolation and aliquoting of CD133+ cells. Patients will receive an infusion of freshly isolated CD133+ cells immediately and frozen doses at days 30 and 60 via peripheral vein (0.2×10(6) cells/kg for each of the three doses). Primary objective is to demonstrate an improvement in the severity of liver disease over 3 months using either G-CSF alone or G-CSF followed by repeated infusions of haematopoietic stem cells compared with standard conservative management. The trial is powered to answer two hypotheses of each treatment compared to control but not powered to detect smaller expected differences between the two treatment groups. As such, the overall α=0.05 for the trial is split equally between the two hypotheses. Conventionally, to detect a relevant standardised effect size of 0.8 point reduction in Model for End-stage Liver Disease score using two-sided α=0.05(overall α=0.1 split equally between the two hypotheses) and 80% power requires 27 participants to be randomised per group (81 participants in total). ETHICS AND DISSEMINATION: The trial is registered at Current Controlled Trials on 18 November 2009 (ISRCTN number 91288089, EuDRACT number 2009-010335-41). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations.

Diagnostic and mechanistic implications of serum free light chains, albumin and alpha-fetoprotein in hepatocellular carcinoma.

BACKGROUND: Mass spectroscopy analysis suggested low serum albumin and high immunoglobulin free light chain (sFLC) levels may have diagnostic value in hepatocellular carcinoma (HCC). Our aims were to apply quantitative assays to confirm these observations, determine their diagnostic utility, and investigate the mechanisms involved. METHODS: Albumin, sFLC, routine liver and renal function tests were measured in patients with chronic liver disease with (n=102) and without (n=113) HCC. The discriminant performance was compared with the current standard serological test alpha-fetoprotein (AFP) using receiver operating characteristic (ROC) and area under the curve (AUC) analyses. RESULTS: sFLC and serum albumin were each confirmed to have discriminatory utility in HCC with AUC values of 0.7 and 0.8, respectively. sFLC were strongly correlated with gammaglobulin levels and both these were inversely related to serum albumin levels. The discriminatory utility of sFLC was retained after adjusting for renal and liver function. CONCLUSIONS: Serum levels of sFLC and albumin were strongly associated with HCC as predicted by mass spectroscopy. Discrimination of HCC by AFP was improved by the addition of either albumin or sFLC. Larger prospective studies are required to determine how AFP, sFLC and albumin might be combined in a useful diagnostic approach for HCC.

Do type 1 receptor tyrosine kinases inform treatment choice? A prospectively planned analysis of the TEAM trial.

BACKGROUND: Epidermal growth factor receptors contribute to breast cancer relapse during endocrine therapy. Substitution of aromatase inhibitors (AIs) may improve outcomes in HER-positive cancers. METHODS: Tissue microarrays were constructed. Quantitative analysis of HER1, HER2, and HER3 was performed. Data were analysed relative to disease-free survival and treatment using outcomes at 2.75 and 6.5 years. RESULTS: Among 4541 eligible samples, 4225 (93%) had complete HER1-3 data. Overall, 5% were HER1-positive, 13% HER2-positive, and 21% HER3-positive; 32% (n=1351) overexpressed at least one HER receptor. In the HER1-3-negative subgroup, the hazard ratio (HR) for upfront exemestane vs tamoxifen at 2.75 years was 0.67 (95% confidence interval (CI), 0.52-0.87), in the HER1-3-positive subgroup, the HR was 1.15 (95% CI, 0.85-1.56). A prospectively planned treatment-by-marker analysis demonstrated a significant interaction between HER1-3 and treatment at 2.75 years (HR=0.58; 95% CI, 0.39-0.87; P=0.008), as confirmed by multivariate regression analysis adjusting for prognostic factors (HR=0.55; 95% CI, 0.36-0.85; P=0.005). This effect was time dependent. CONCLUSION: In the 2.75 years prior to switching patients initially treated with tamoxifen to exemestane, a significant treatment-by-marker effect exists between AI/tamoxifen treatment and HER1-3 expression, suggesting HER expression could be used to select appropriate endocrine treatment at diagnosis to prevent or delay early relapses.

A randomised controlled trial to evaluate both the role and the optimal fractionation of radiotherapy in the conservative management of early breast cancer.

AIMS: Postoperative radiotherapy is routinely used in early breast cancer employing either 50 Gy in 25 daily fractions (long course) or 40 Gy in 15 daily fractions (short course). The role of radiotherapy and shorter fractionation regimens require validation. MATERIALS AND METHODS: Patients with clinical stage I and II disease were randomised to receive immediate radiotherapy or delayed salvage treatment (no radiotherapy). Patients receiving radiotherapy were further randomised between long (50 Gy in 25 daily fractions) or short (40 Gy in 15 daily fractions) regimens. The primary outcome measure was time to first locoregional relapse. Reported results are at a median follow-up of 16.9 years (interquartile range 15.4-18.8). RESULTS: In total, 707 women were recruited between 1985 and 1992: median age 59 years (range 28-80), 68% postmenopausal, median tumour size 2.0 cm (range 0.12-8.0); 271 patients have relapsed: 110 radiotherapy, 161 no radiotherapy. The site of first relapse was locoregional158 (64%) and distant 87 (36%). There was an estimated 24% reduction in the risk of any competing event (local relapse, distant relapse or death) with radiotherapy (hazard ratio = 0.76; 95% confidence interval 0.65, 0.88). The benefit of radiotherapy treatment for all competing event types was statistically significant (X(Wald)(2) = 36.04, P < 0.001). Immediate radiotherapy reduced the risk of locoregional relapse by 62% (hazard ratio = 0.38; 95% confidence interval 0.27, 0.53), consistent across prognostic subgroups. No differences were seen between either radiotherapy fractionation schedules. CONCLUSIONS: This study confirmed better locoregional control for patients with early breast cancer receiving radiotherapy. A radiotherapy schedule of 40 Gy in 15 daily fractions is an efficient and effective regimen that is at least as good as the international conventional regimen of 50 Gy in 25 daily fractions.

Serum matrix metalloproteinase 9 and colorectal neoplasia: a community-based evaluation of a potential diagnostic test.

BACKGROUND: A blood test may be a more acceptable routine colorectal cancer (CRC) screening test than faecal occult blood test, flexible sigmoidoscopy or colonoscopy, and could be safer and cheaper. We evaluated the accuracy of a serum matrix metalloproteinase (MMP9) test for CRC in a non-presenting symptomatic population. METHODS: A cohort, aged 50-69 with lower gastrointestinal symptoms, was identified by community-based survey. Accuracy of serum MMP9 was assessed by comparison with colonoscopy. Logistic regression identified predictors of neoplasia and receiver operating characteristic curve analyses determined the cutoff to maximise the sensitivity. RESULTS: Data were available for 748 patients. Overall, 46 cases of neoplasia were identified. Univariate analysis demonstrated that demographic characteristics, behavioural factors, clinical symptoms and raised serum MMP9 concentration were all significantly associated with the presence of neoplasia. Our final logistic regression model had a sensitivity of 79% and specificity of 70%. CONCLUSION: We demonstrated a significant association between serum MMP9 concentration and the presence of neoplasia. Serum MMP9 levels are raised in those with cancer and high-risk adenomas, although MMP9 estimation is likely to have the greatest predictive utility when used as part of a panel of biomarkers. Further work is required to identify biomarkers that are sufficiently accurate for implementing into routine practice.

Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials.

The ESPAC-1, ESPAC-1 plus, and early ESPAC-3(v1) results (458 randomized patients; 364 deaths) were used to estimate the effectiveness of adjuvant 5FU/FA vs resection alone for pancreatic cancer using meta-analysis. The pooled hazard ratio of 0.70 (95% CI=0.55-0.88) P=0.003, and the median survival of 23.2 (95% CI=20.1-26.5) months with 5FU/FA vs 16.8 (95% CI=14.3-19.2) months with resection alone supports the use of adjuvant 5FU/FA in pancreatic cancer.

Modelling prognostic factors in advanced pancreatic cancer.

Pancreatic cancer is the fifth most common cause of cancer death. Identification of defined patient groups based on a prognostic index may improve the prediction of survival and selection of therapy. Many prognostic factors have been identified often based on retrospective, underpowered studies with unclear analyses. Data from 653 patients were analysed. Continuous variables are often simplified assuming a linear relationship with log hazard or introducing a step function (dichotomising). Misspecification may lead to inappropriate conclusions but has not been previously investigated in pancreatic cancer studies. Models based on standard assumptions were compared with a novel approach using nonlinear fractional polynomial (FP) transformations. The model based on FP-transformed covariates was most appropriate and confirmed five previously reported prognostic factors: albumin, CA 19-9, alkaline phosphatase, LDH and metastases, and identified three additional factors not previously reported: WBC, AST and BUN. The effects of CA 19-9, alkaline phosphatase, AST and BUN may go unrecognised due to simplistic assumptions made in statistical modelling. We advocate a multivariable approach that uses information contained within continuous variables appropriately. The functional form of the relationship between continuous covariates and survival should always be assessed. Our model should aid individual patient risk stratification and the design and analysis of future trials in pancreatic cancer.

Elevated serum matrix metalloproteinase 9 (MMP-9) concentration predicts the presence of colorectal neoplasia in symptomatic patients.

Early detection of polyps or colorectal carcinoma can reduce colorectal carcinoma-associated deaths. Previous studies have demonstrated raised serum levels of matrix metalloproteinase 9 (sMMP-9) in a range of cancers. The aim of this study was to investigate the role of sMMP-9 levels in identifying colorectal neoplasia. Consenting patients donated a blood sample and were assessed by proforma-led history and physical examination. Samples were analysed for sMMP-9 concentration (enzyme-linked immuno-sorbant assay) and compared to final diagnoses. Logistic regression modelling determined independent factors associated with neoplasia. A total of 365 patients were recruited of whom 300 were analysed, including 46 normal controls. A total of 27 significant adenomas and 63 malignancies were identified. The median sMMP-9 concentration was 443 ng ml(-1) (IQR: 219-782; mean: 546). Patients with neoplasia had significantly elevated sMMP-9 levels (P<0.001). Logistic regression modelling identified elevated log(sMMP-9) as the most significant predictor of neoplasia (chi(2)=38.33, P<0.001). Other significant factors were age, sex, smoking history, abdominal pain and weight loss. The model accurately predicted neoplasia in 77.3% of cases. Sensitivity and specificity were 77.9 and 77.1%. sMMP-9 estimation can accurately stratify patient to low- or high-risk cohorts. Serum sampling is a potential means of avoiding unnecessary colonoscopy and reducing patient anxiety, iatrogenic morbidity and mortality, and cost.

Influence of surgical resection and post-operative complications on survival following adjuvant treatment for pancreatic cancer in the ESPAC-1 randomized controlled trial.

BACKGROUND/AIMS: The influence of type of surgery and occurrence of post-operative complications on survival following adjuvant therapy for pancreatic cancer are uncertain. METHODS: Cox proportional hazard modelling was used to investigate the influence of type of surgery and the presence of complications on survival in conjunction with clinico-pathological variables in the 550 patients of the ESPAC-1 adjuvant randomized controlled trial. RESULTS: Standard Kausch-Whipple (KW) was performed in 282 (54%) patients, 186 (35%) had a pylorus-preserving (PP) KW, 39 (7%) had a distal pancreatectomy and 21 (4%) had a total pancreatectomy. Post-operative complications were reported in 140 (27%) patients. PP-KW patients survived longer with a median (95% CI) survival of 19.9 (17.3, 23.1) months compared to 14.8 (13.0, 16.7) for KW patients (chi(2)(LR) = 15.1, p < 0.001). KW patients were more likely however to have R1 margins (67 (24%) vs. 29 (16%), chi(2) = 4.59, p = 0.032), poorly differentiated tumours (70 (26%) vs. 19 (10%), chi(2) = 18.65, p < 0.001) and positive lymph nodes (165 (60%) vs. 81 (44%), chi(2) = 11.32, p < 0.001). Post-operative complications did not significantly affect survival. Independent prognostic factors were tumour grade, nodal status and tumour size but not type of surgery or post-operative complications. There was a survival benefit for chemotherapy irrespective of the type of surgery or post-operative complications. CONCLUSIONS: The KW and PP-KW procedures did not significantly influence the hazard of death in the presence of tumour staging, demonstrating that ESPAC-1 surgeons showed good judgement in their choice of operation. Post-operative complications did not adversely affect the survival benefit from adjuvant chemotherapy.