WT1 expression in vessels varies with histopathological grade in tumour-bearing and control tissue from patients with breast cancer.

BACKGROUND: The Wilms' tumour protein (WT1), which influences tumour development and angiogenesis, is a promising therapeutic target in breast cancer. We hypothesised that WT1 expression would vary in endothelial cells in distinct sub-classifications of breast cancer. METHODS: WT1 expression and vascular density were quantified by immunohistochemical analysis of human (n = 57) and murine breast cancers. Human tumours were sub-classified by histopathological grade, ER status and HER2 enrichment. RESULTS: WT1 was identified in endothelial (and epithelial and smooth muscle) cells in tumours and tumour-free tissues (controls) from patients and mice with breast cancer. WT1 expression was higher in tumours than in controls, but this was not due to increased endothelial WT1. Vascular WT1 in cancers decreased as histopathological grade increased. WT1 was higher in ER-positive versus ER-negative cancers. Strikingly, reduced WT1 expression in controls correlated with an increased Nottingham Prognostic Index score. CONCLUSIONS: Expression of WT1 is increased in breast cancers but this is not limited to the vascular compartment. The association between reduced WT1 in tumour-free tissue and poor prognosis suggests a protective role for WT1 in the healthy breast.

Intraoperative assessment of the curative potential to predict survival after gastric cancer resection: A national cohort study.

BACKGROUND: The surgeon's intraoperative assessment of the curative potential of tumor resection following gastrectomy adds new information that could help clinicians and patients by predicting survival. METHODS: All patients in Sweden undergoing gastric cancer resection between 2006 and 2018 were grouped according to a prospectively registered variable; the surgeon's intraoperative assessment of the curative potential of surgery: curative, borderline curative, or palliative. Factors affecting group allocation were analyzed with multivariable logistic regression, while survival was analyzed using multivariable Cox regression and the Kaplan-Meier method. Positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: Of 2341 patients undergoing gastric cancer resection, 1547 (71%) were deemed curative, 340 (15%) borderline curative, and 314 (14%) palliative (140 missing assessments). Advanced stage increased the risk of borderline curative resection (Stage III, odds ratio (OR) = 6.04, 95% confidence interval (CI) = 3.92-9.31), as did emergency surgery OR = 3.31 (1.74-6.31) and blood loss >500 mL; OR = 1.63 (1.06-2.49). Neoadjuvant chemotherapy and multidisciplinary team (MDT) discussion both decreased the risk of borderline curative resection, OR = 0.58 (0.39-0.87) and 0.57 (0.40-0.80), respectively. In multivariable Cox regression, the surgeon's assessment independently predicted worse survival for borderline curative (hazard ratio (HR) = 1.54, 95% CI = 1.29-1.83) and palliative resections (HR = 1.76, 95% CI = 1.45-2.19), compared to curative resections. The sensitivity of the surgeon's assessment of long-term survival was 96.7%. The PPV was 50.7% and the NPV was 92.1%. CONCLUSION: The surgeon's intraoperative assessment of the curative potential of gastric cancer surgery may independently aid survival prediction and is analogous to prognostication by pathologic Staging. Advanced disease, emergency surgery, and a high intraoperative blood loss, increases the risk of a borderline curative or palliative resection. Conversely, neoadjuvant treatment and MDT discussion reduce the risk of borderline curative or palliative resection.

Textbook outcomes for oesophagectomy: A valid composite measure assessment tool for surgical performance in a specialist unit.

INTRODUCTION: In 2017 the Dutch Upper Gastrointestinal Cancer Audit Group proposed a ten-item composite measure for a 'textbook outcome' (TBO) following oesophago-gastric resection. Studies have shown associations between TBO and improved conditional and overall survival. The aim of this study was to evaluate the use of TBO to assess the outcomes from a single specialist unit in a country, with low incidence of disease, allowing comparisons with international specialist centres. MATERIALS AND METHODS: Retrospective analysis of prospectively collected oesophageal cancer surgery data at a single centre, in Australia, between 2013 and 2018. Multivariable logistical regression assessed association between baseline factors and TBO. Post-operative complications were analysed in two separate groups as Clavien-Dindo ≥2 (CD ≥ 2) and Clavien-Dindo ≥3 (CD ≥ 3). Cox-proportional hazards regression analysis determined the association between TBO and survival. RESULTS: 246 patients were analysed, with 50.8% (n = 125) achieving a TBO when complications were defined as CD ≥ 2 and 58.9% (n = 145) when using CD ≥ 3. Patients aged ≥75, and those with a pre-operative respiratory co-morbidity were less likely to achieve a TBO. Overall survival was not influenced by TBO when complications were defined as CD ≥ 2, however it was higher when a TBO was achieved, and complications were defined as CD ≥ 3 (HR 0.54, 95% CI, 0.35 to 0.84, P = 0.007). CONCLUSION: TBO is a multi-parameter metric that allowed benchmarking of the quality of oesophageal cancer surgery in our unit, providing favourable outcomes compared with other published data. There was an association between TBO and improved overall survival when the definition of severe complications was CD ≥ 3.

Relaxing music for anxiety control.

The purpose of this investigation was to determine the characteristics of relaxing music for anxiety control. Undergraduate students (N=84) were instructed to imagine themselves in an anxiety producing situation while listening to a selection of 30 music compositions. For each composition, level of relaxation, the factors that either enhanced or detracted from its relaxing potential and the emotional labels attached were assessed. Participants were also asked to state which music components (e.g., tempo, melody) were most conducive to relaxation. Additional information was obtained through the use of a focus group of 6 undergraduate music students. This paper presents details on the characteristics of relaxing-music for anxiety control and emotional labels attached to the relaxing compositions. Furthermore, an importance value has been attached to each of the music components under scrutiny, thus providing an indication of which music components should receive greatest attention when selecting music for anxiety control.

Improving the working environment for the delivery of safe surgical care in the UK: a qualitative cross-sectional analysis.

OBJECTIVES: The aim of this study was to identify current problems and potential solutions to improve the working environment for the delivery of safe surgical care in the UK. DESIGN: Prospective, questionnaire-based cross-sectional study. SETTING/PARTICIPANTS: Following validation, an electronic questionnaire was distributed to postgraduate local education and training board distribution lists, the Royal College of Surgeons of Edinburgh (RCSEd) mailing lists and trainee organisations. This consisted of a single open-ended question inviting five open-ended responses. Throughout the 13-week study period, the survey was also published on a number of social media platforms. RESULTS: A total of 505 responders completed the survey, of which 35% were consultants, 30% foundation doctors, 17% specialty trainees, 11% specialty doctors, 5% core trainees and <1% surgical nurse practitioners. A total of 2238 free-text answers detailed specific actions to improve the working environment. These responses were individually coded and then grouped into nine categories (staff resources, non-staff resources, support, working conditions, communication and team work, systems improvement, patient centred, training and education, and miscellaneous). CONCLUSIONS: The results of this study have identified a number of key areas that, if addressed, may improve the environment for the delivery of safer surgical care. Common themes that emerged across all grades included: increased front-line staff; a return to a 'firm' structure to improve team continuity; greater senior support; and improved hospital facilities to help staff rest and recuperate. While unlimited funding remains unrealistic, many of the suggestions could be implemented in a cost-neutral fashion and include insightful ideas for remodelling or restructuring the workforce to improve the efficiency of the surgical team. The findings of this study formed the basis of a set of recommendations published by the RCSEd as a discussion paper.

Randomised controlled non-inferiority trial of primary care-based facilitated access to an alcohol reduction website.

BACKGROUND: Brief interventions (BIs) delivered in primary care have been shown to be effective in reducing risky drinking, but implementation is limited. Facilitated access to a digital application offers a novel alternative to face-to-face intervention, but its relative effectiveness is unknown. METHODS: Primary care-based, non-inferiority, randomised controlled trial comparing general practitioner (GP) facilitated access to an interactive alcohol reduction website (FA) with face-to-face BI for risky drinking. Patients screening positive on the short Alcohol Use Disorders Identification Test (AUDIT-C) were invited to participate in the trial. Assessment at baseline, 3 months and 12 months was carried out using AUDIT and EQ-5D-5L questionnaires. FINDINGS: 58 participating GPs approached 9080 patients of whom 4529 (49.9%) logged on, 3841 (84.8%) undertook screening, 822 (21.4%) screened positive and 763 (19·9%) were recruited. 347 (45.5%) were allocated to FA and 416 (54.5%) to BI. At 3 months, subjects in FA group with an AUDIT score of ≥8 reduced from 95 (27.5%) to 85 (26.8%) while those in BI group increased from 123 (20.6%) to 141 (37%). Differences between groups were principally due to responses to AUDIT question 10. Analysis of primary outcome indicated non-inferiority of FA compared with BI, and prespecified subgroup analysis indicated benefits for older patients and those with higher levels of computer literacy and lower baseline severity. Additional analyses undertaken to take account of bias in response to AUDIT question 10 failed to support non-inferiority within the prespecified 10% boundary. INTERPRETATION: Prespecified protocol-driven analyses of the trial indicate that FA is non-inferior to BI; however, identified bias in the outcome measure and further supportive analyses question the robustness of this finding. It is therefore not possible to draw firm conclusions from this trial, and further research is needed to determine whether the findings can be replicated using more robust outcome measures. TRIAL REGISTRATION NUMBER: NCT01638338; Results.

Randomised controlled non-inferiority trial of primary care-based facilitated access to an alcohol reduction website: cost-effectiveness analysis.

OBJECTIVES: To evaluate the 12-month costs and quality-adjusted life years (QALYs) gained to the Italian National Health Service of facilitated access to a website for hazardous drinkers compared with a standard face-to-face brief intervention (BI). DESIGN: Randomised 1:1 non-inferiority trial. SETTING: Practices of 58 general practitioners (GPs) in Italy. PARTICIPANTS: Of 9080 patients (>18 years old) approached to take part in the trial, 4529 (49·9%) logged on to the website and 3841 (84.8%) undertook online screening for hazardous drinking. 822 (21.4%) screened positive and 763 (19.9%) were recruited to the trial. INTERVENTIONS: Patients were randomised to receive either a face-to-face BI or access via a brochure from their GP to an alcohol reduction website (facilitated access). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is the cost per QALY gained of facilitated access compared with face-to-face. A secondary analysis includes total costs and benefits per 100 patients, including number of hazardous drinkers prevented at 12 months. RESULTS: The average time required for the face-to-face BI was 8 min (95% CI 7.5 min to 8.6 min). Given the maximum time taken for facilitated access of 5 min, face-to-face is an additional 3 min: equivalent to having time for another GP appointment for every three patients referred to the website. Complete case analysis adjusting for baseline the difference in QALYs for facilitated access is 0.002 QALYs per patient (95% CI -0.007 to 0.011). CONCLUSIONS: Facilitated access to a website to reduce hazardous drinking costs less than a face-to-face BI given by a GP with no worse outcomes. The lower cost of facilitated access, particularly in regards to investment of time, may facilitate the increase in provision of BIs for hazardous drinking. TRIAL REGISTRATION NUMBER: NCT01638338;Post-results.

In Vivo Assays for Assessing the Role of the Wilms' Tumor Suppressor 1 (Wt1) in Angiogenesis.

The Wilms' tumor suppressor gene (WT1) is widely expressed during neovascularization, but it is almost entirely absent in quiescent adult vasculature. However, in vessels undergoing angiogenesis, WT1 is dramatically upregulated. Studies have shown Wt1 has a role in both tumor and ischemic angiogenesis, but the mechanism of Wt1 action in angiogenic tissue remains to be elucidated. Here, we describe two methods for induction of in vivo angiogenesis (subcutaneous sponge implantation, femoral artery ligation) that can be used to assess the influence of Wt1 on new blood vessel formation. Subcutaneously implanted sponges stimulate an inflammatory and fibrotic response including cell infiltration and angiogenesis. Femoral artery ligation creates ischemia in the distal hindlimb and produces an angiogenic response to reperfuse the limb which can be quantified in vivo by laser Doppler flowmetry. In both of these models, the role of Wt1 in the angiogenic process can be assessed using histological/immunohistochemical staining, molecular analysis (qPCR) and flow cytometry. Furthermore, combined with suitable genetic modifications, these models can be used to explore the causal relationship between Wt1 expression and angiogenesis and to trace the lineage of cells expressing Wt1. This approach will help to clarify the importance of Wt1 in regulating neovascularization in the adult, and its potential as a therapeutic target.

What shape do UK trainees want their training to be? Results of a cross-sectional study.

OBJECTIVES: The British Government is acting on recommendations to overhaul postgraduate training to meet the needs of the changing population, to produce generalist doctors undergoing shorter broad-based training (Greenaway Review). Only 45 doctors in training were involved in the consultation process. This study aims to obtain a focused perspective on the proposed reforms by doctors in training from across specialities. DESIGN: Prospective, questionnaire-based cross-sectional study. SETTING/PARTICIPANTS: Following validation, a 31-item electronic questionnaire was distributed via trainee organisations and Postgraduate Local Education and Training Board (LETB) mailing lists. Throughout the 10-week study period, the survey was publicised on several social media platforms. RESULTS: Of the 3603 demographically representative respondents, 69% knew about proposed changes. Of the respondents, 73% expressed a desire to specialise, with 54% keen to provide general emergency cover. A small proportion (12%) stated that current training pathway length is too long, although 86% felt that it is impossible to achieve independent practitioner-level proficiency in a shorter period of time than is currently required. Opinions regarding credentialing were mixed, but tended towards disagreement. The vast majority (97%) felt credentialing should not be funded by doctors in training. Respondents preferred longer placement lengths with increasing career progression. Doctors in training value early generalised training (65%), with suggestions for further improvement. CONCLUSIONS: This is the first large-scale cross-specialty study regarding the Shape of Training Review. Although there are recommendations which trainees support, it is clear that one size does not fit all. Most trainees are keen to provide a specialist service on an emergency generalist background. Credentialing is a contentious issue; however, we believe removing aspects from curricula into post-Certificate of Completion of Training (CCT) credentialing programmes with shortened specialty training routes only degrades the current consultant expertise, and does not serve the population. Educational needs, not political winds, should drive changes in postgraduate medical education and all stakeholders should be involved.

A randomised controlled non-inferiority trial of primary care-based facilitated access to an alcohol reduction website (EFAR-FVG): the study protocol.

INTRODUCTION: There is a strong body of evidence demonstrating the effectiveness of brief interventions by primary care professionals for risky drinkers. However, implementation levels remain low because of time constraints and other factors. Facilitated access to an alcohol reduction website offers primary care professionals a time-saving alternative to standard face-to-face intervention, but it is not known whether it is as effective. METHODS AND ANALYSIS: A randomised controlled non-inferiority trial for risky drinkers comparing facilitated access to a dedicated website with standard face-to-face brief intervention to be conducted in primary care settings in the Region of Friuli Giulia Venezia, Italy. Adult patients will be given a leaflet inviting them to log on to a website to complete the Alcohol Use Disorders Identification Test (AUDIT-C) alcohol screening questionnaire. Screen positives will be requested to complete an online trial module including consent, baseline assessment and randomisation to either standard intervention by the practitioner or facilitated access to an alcohol reduction website. Follow-up assessment of risky drinking will be undertaken online at 1 month, 3 months and 1 year using the full AUDIT questionnaire. Proportions of risky drinkers in each group will be calculated and non-inferiority assessed against a specified margin of 10%. Assuming a reduction of 30% of risky drinkers receiving standard intervention, 1000 patients will be required to give 90% power to reject the null hypothesis. ETHICS AND DISSEMINATION: The protocol was approved by the Isontina Independent Local Ethics Committee on 14 June 2012. The findings of the trial will be disseminated through peer-reviewed journals, national and international conference presentations and public events involving the local administrations of the towns where the trial participants are resident. REGISTRATION DETAILS: Trial registration number NCT: 01638338.

Glioma pathophysiology: insights emerging from proteomics.

Proteomics is increasingly employed in both neurological and oncological research to provide insight into the molecular basis of disease but rarely has a coherent, novel pathophysiological insight emerged. Gliomas account for >50% of adult primary intracranial tumors, with malignant gliomas (anaplastic astrocytomas and glioblastoma multiforme) being the most common. In glioma, the application of proteomic technology has identified altered protein expression but without consistency of these alterations or their biological significance being established. A systematic review of multiple independent proteomic analyses of glioma has demonstrated alterations of 99 different proteins. Importantly 10 of the 99 proteins found differentially expressed in glioma [PHB, Hsp20, serum albumin, epidermal growth factor receptor (EGFR), EA-15, RhoGDI, APOA1, GFAP, HSP70, PDIA3] were identified in multiple publications. An assessment of protein-protein interactions between these proteins compiled using novel web-based technology, revealed a robust and cohesive network for glioblastoma. The protein network discovered (containing TP53 and RB1 at its core) compliments recent findings in genomic studies of malignant glioma. The novel perspective provided by network analysis indicates that the potential of this technology to explore crucial aspects of glioma pathophysiology can now be realized but only if the conceptual and technical limitations highlighted in this review are addressed.

Bronchial flap closure of the right lower lobe bronchus.

We describe a novel method for closure of the bronchus intermedius, after right lower lobectomy, using a flap derived from the lower lobe apical segmental bronchus. We have successfully used this technique in an endobronchial carcinoid tumor occurring in a young man. It allowed middle lobe preservation despite a very proximal tumor position within the basal trunk bronchus. Adequate tumor margins were confirmed by on-table frozen section examination. This technique may have particular use in carcinoids or benign tumors.

The utility of functional interaction and cluster analysis in CNS proteomics.

Proteomic studies offer enormous potential for gaining insight into cellular dynamics and disease processes. An immediate challenge for enhancing the utility of proteomics in translational research lies in methods of handling and interpreting the large datasets generated. Publications rarely extend beyond lists of proteins, putatively altered derived from basic statistics. Here we describe two additional distinct approaches (with particular strengths and limitations) that will enhance the analysis of proteomic datasets. Arithmetic and functional cluster analyses have been performed on proteins found differentially regulated in human glioma. These two approaches highlight (i) subgroups of proteins that may be co-regulated and play a role in glioma pathophysiology, and (ii) functional protein interactions that may improve comprehension of the biological mechanisms involved. A coherent proteomic strategy which involves both arithmetic and functional clustering, (together with careful consideration of conceptual limitations), is imperative for quantitative proteomics to deliver and advance the biological understanding of disease of the CNS. A strategy which combines arithmetic analysis and bioinformatics of protein-protein interactions is both generally applicable and will facilitate the interpretation of proteomic data.