Making an IMPACT: A priority setting consultation exercise to improve outcomes in patients with locally advanced, recurrent and metastatic colorectal cancer.

AIM: The IMPACT (Improving the Management of Patients with Advanced Colorectal Tumours) initiative was established by the Association of Coloproctology of Great Britain and Ireland in 2017 as a consortium of surgeons (colorectal, hepatobiliary, thoracic), oncologists, radiologists, pathologists, palliative care physicians, patients, carers and charity stakeholders who will work together to improve outcomes in patients with advanced and metastatic colorectal cancer. To establish this initiative, better information is required to establish how further intervention is focused. This paper details the approaches used, and outcomes generated, from a priority setting exercise to inform the design of the IMPACT initiative. METHODS: A mixed method approach was employed to set the priorities of patients, clinicians and other key stakeholders in the delivery of optimal care. This consisted of two patient centered consultation events and a questionnaire. RESULTS: A total of 128 participants took part in the consultation exercise; 15 patients, 5 carers/family members, 5 charity representatives and 113 healthcare professionals. Nine key themes for focus were identified, these were: current service provision, specialist services, communication, education, access to care, definitions and standardisation, research and audit, outcome measures, and funding of specialist care. CONCLUSION: These future priorities will be developed with collaborative engagement in a systematic manner to produce an overall cohesive programme which will deliver a sustainable and efficient clinical and academic service to improving the management of patients with advanced colorectal tumours.

Systematic review of definitions and outcome measures for return of bowel function after gastrointestinal surgery.

Background: Ileus is common after gastrointestinal surgery and has been identified as a research priority. Several issues have limited previous research, including a widely accepted definition and agreed outcome measure. This review is the first stage in the development of a core outcome set for the return of bowel function after gastrointestinal surgery. It aims to characterize the extent of variation in current outcome reporting. Methods: A systematic search of MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and the Cochrane Library was performed for 1990-2017. RCTs of adults undergoing gastrointestinal surgery, including at least one reported measure relating to return of bowel function, were eligible. Trial registries were searched across the same period for ongoing and completed (but not published) RCTs. Definitions of ileus and outcome measures describing the return of bowel function were extracted. Results: Of 5670 manuscripts screened, 215 (reporting 217 RCTs) were eligible. Most RCTs involved patients undergoing colorectal surgery (161 of 217, 74·2 per cent). A total of 784 outcomes were identified across all published RCTs, comprising 73 measures (clinical: 63, 86 per cent; radiological: 6, 8 per cent; physiological: 4, 5 per cent). The most commonly reported outcome measure was 'time to first passage of flatus' (140 of 217, 64·5 per cent). The outcomes 'ileus' and 'prolonged ileus' were defined infrequently and variably. Conclusion: Outcome reporting for the return of bowel function after gastrointestinal surgery is variable and not fit for purpose. An agreed core outcome set will improve the consistency, reliability and clinical value of future studies.

Socioeconomic differences in selection for liver resection in metastatic colorectal cancer and the impact on survival.

BACKGROUND: Socioeconomic inequalities in colorectal cancer (CRC) survival are well recognised. The aim of this study was to describe the impact of socioeconomic deprivation on survival in patients with synchronous CRC liver-limited metastases, and to investigate if any survival inequalities are explained by differences in liver resection rates. METHODS: Patients in the National Bowel Cancer Audit diagnosed with CRC between 2010 and 2016 in the English National Health Service were included. Linked Hospital Episode Statistics data were used to identify the presence of liver metastases and whether a liver resection had been performed. Multivariable random-effects logistic regression was used to estimate the odds ratio (OR) of liver resection by Index of Multiple Deprivation (IMD) quintile. Cox-proportional hazards model was used to compare 3-year survival. RESULTS: 13,656 patients were included, of whom 2213 (16.2%) underwent liver resection. Patients in the least deprived IMD quintile were more likely to undergo liver resection than those in the most deprived quintile (adjusted OR 1.42, 95% confidence interval (CI) 1.18-1.70). Patients in the least deprived quintile had better 3-year survival (least deprived vs. most deprived quintile, 22.3% vs. 17.4%; adjusted hazard ratio (HR) 1.20, 1.11-1.30). Adjusting for liver resection attenuated, but did not remove, this effect. There was no difference in survival between IMD quintile when restricted to patients who underwent liver resection (adjusted HR 0.97, 0.76-1.23). CONCLUSIONS: Deprived CRC patients with synchronous liver-limited metastases have worse survival than more affluent patients. Lower rates of liver resection in more deprived patients is a contributory factor.

The timing of liver resection in patients with colorectal cancer and synchronous liver metastases: a population-based study of current practice and survival.

AIM: There is uncertainty regarding the optimal sequence of surgery for patients with colorectal cancer (CRC) and synchronous liver metastases. This study was designed to describe temporal trends and inter-hospital variation in surgical strategy, and to compare long-term survival in a propensity score-matched analysis. METHOD: The National Bowel Cancer Audit dataset was used to identify patients diagnosed with primary CRC between 1 January 2010 and 31 December 2015 who underwent CRC resection in the English National Health Service. Hospital Episode Statistics data were used to identify those with synchronous liver-limited metastases who underwent liver resection. Survival outcomes of propensity score-matched groups were compared. RESULTS: Of 1830 patients, 270 (14.8%) underwent a liver-first approach, 259 (14.2%) a simultaneous approach and 1301 (71.1%) a bowel-first approach. The proportion of patients undergoing either a liver-first or simultaneous approach increased over the study period from 26.8% in 2010 to 35.6% in 2015 (P < 0.001). There was wide variation in surgical approach according to hospital trust of diagnosis. There was no evidence of a difference in 4-year survival between the propensity score-matched cohorts according to surgical strategy: bowel first vs simultaneous [hazard ratio (HR) 0.92 (95% CI: 0.80-1.06)] or bowel first vs liver first [HR 0.99 (95% CI: 0.82-1.19)]. CONCLUSION: There is evidence of wide variation in surgical strategy in dealing with CRC and synchronous liver metastases. In selected patients, the simultaneous and liver-first strategies have comparable long-term survival to the bowel-first approach.

Impact of hepatobiliary service centralization on treatment and outcomes in patients with colorectal cancer and liver metastases.

BACKGROUND: Centralization of specialist surgical services can improve patient outcomes. The aim of this cohort study was to compare liver resection rates and survival in patients with primary colorectal cancer and synchronous metastases limited to the liver diagnosed at hepatobiliary surgical units (hubs) with those diagnosed at hospital Trusts without hepatobiliary services (spokes). METHODS: The study included patients from the National Bowel Cancer Audit diagnosed with primary colorectal cancer between 1 April 2010 and 31 March 2014 who underwent colorectal cancer resection in the English National Health Service. Patients were linked to Hospital Episode Statistics data to identify those with liver metastases and those who underwent liver resection. Multivariable random-effects logistic regression was used to estimate the odds ratio of liver resection by presence of specialist hepatobiliary services on site. Survival curves were estimated using the Kaplan-Meier method. RESULTS: Of 4547 patients, 1956 (43·0 per cent) underwent liver resection. The 1081 patients diagnosed at hubs were more likely to undergo liver resection (adjusted odds ratio 1·52, 95 per cent c.i. 1·20 to 1·91). Patients diagnosed at hubs had better median survival (30·6 months compared with 25·3 months for spokes; adjusted hazard ratio 0·83, 0·75 to 0·91). There was no difference in survival between hubs and spokes when the analysis was restricted to patients who had liver resection (P = 0·620) or those who did not undergo liver resection (P = 0·749). CONCLUSION: Patients with colorectal cancer and synchronous metastases limited to the liver who are diagnosed at hospital Trusts with a hepatobiliary team on site are more likely to undergo liver resection and have better survival.

A collaborative review of the current concepts and challenges of anastomotic leaks in colorectal surgery.

The reduction of the incidence, detection and treatment of anastomotic leakage (AL) continues to challenge the colorectal surgical community. AL is not consistently defined and reported in clinical studies, its occurrence is variably reported and its impact on longterm morbidity and health-care resources has received relatively little attention. Controversy continues regarding the best strategies to reduce the risk. Diagnostic tests lack sensitivity and specificity, resulting in delayed diagnosis and increased morbidity. Intra-operative fluorescence angiography has recently been introduced as a means of real-time assessment of anastomotic perfusion and preliminary evidence suggests that it may reduce the rate of AL. In addition, concepts are emerging about the role of the rectal mucosal microbiome in AL and the possible role of new prophylactic therapies. In January 2016 a meeting of expert colorectal surgeons and pathologists was held in London, UK, to identify the ongoing controversies surrounding AL in colorectal surgery. The outcome of the meeting is presented in the form of research challenges that need to be addressed.

The evolution of intraoperative conversion in video assisted thoracoscopic lobectomy.

INTRODUCTION Unplanned conversion to thoracotomy remains a major concern in video assisted thoracoscopic surgery (VATS) lobectomy. This study aimed to investigate the development of a VATS lobectomy programme over a five-year period, with a focus on the causes and consequences of unplanned conversions. METHODS A single centre retrospective review was performed of patients who underwent complete anatomical lung resection initiated by VATS between January 2010 and April 2015. RESULTS In total, 1,270 patients underwent a lobectomy in the study period and 684 (53.9%) of these were commenced thoracoscopically. There were 75 cases (10.9%) with unplanned conversion. The proportion of lobectomies started as VATS was significantly higher in the second half of the study period (2010-2012: 277/713 [38.8%], 2013-2015: 407/557 [73.1%], p<0.001). The conversion rate dropped initially from 20.4% (11/54) in 2010 to 9.9% (15/151) in 2013 and then remained consistently under 10% until 2015. Conversions were most commonly secondary to vascular injury (26/75, 34.7%). Patients undergoing unplanned conversion had a longer length of stay than VATS completed patients (9 vs 6 days, p<0.001). There was a higher incidence of respiratory failure (10/75 [14.1%] vs 23/607 [3.8%], p<0.001) and 30-day mortality (7/75 [9.3%] vs 6/607 [1.0%], p=0.003) in patients with unplanned conversion than in those with completed VATS. CONCLUSIONS As our VATS lobectomy programme developed, the unplanned conversion rate dropped initially and then remained constant at approximately 10%. With increasing unit experience, it is both safe and technically possible to complete the majority of lobectomy procedures thoracoscopically.

Diverse applications for near infra-red intraoperative imaging.

BACKGROUND: Near infra-red angiography using Indocyanine Green (ICG) has increasingly used as a tool for intraoperative diagnostics. AIMS: The aim of this review is to explore the applications of ICG fluorescence angiography with particular emphasis on general surgical applications. MATERIALS AND METHODS: A literature review was conducted to identify and summarise the diverse range of applications of ICG fluorescence. RESULTS: ICG fluorescence angiography is increasingly used in a number of general surgical applications, including identification of colorectal liver metastases, assessment of skin flap perfusion, diagnosis of peritoneal endometriosis, ureteric identification, and localisation of colonic pathology. DISCUSSION: ICG fluorescence angiography has clinical application in many areas as a tool for guiding surgical resection. CONCLUSION: With the technological developments in near infra-red imaging it is likely that ICG fluorescence will play an increasing role in many routine surgical procedures.

Prognostic factors and survival after resection of colorectal liver metastasis in the era of preoperative chemotherapy: an 11-year single-centre study.

INTRODUCTION: A variety of factors have been identified in the literature which influence survival following resection of colorectal liver metastases (CRLM). Much of this literature is historical, and its relevance to contemporary practice is not known. The aim of this study was to identify those factors which influence survival during the era of preoperative chemotherapy in patients undergoing resection of CRLM in a UK centre. METHODS: All patients having liver resection for CRLM during an 11-year period up to 2011 were identified from a prospectively maintained database. Prognostic factors analysed included tumour size (≥5 or <5 cm), lymph node status of the primary tumour, margin positivity (R1; <1 mm), neo-adjuvant chemotherapy (for liver), tumour differentiation, number of liver metastases (≥4), preoperative carcinoembryonic antigen (CEA; ≥200 ng/ml) and whether metastases were synchronous (i.e. diagnosed within 12 months of colorectal resection) or metachronous to the primary tumour. Overall survival (OS) was compared using Kaplan-Meier plots and a log rank test for significance. Multivariate analysis was performed using a Cox regression model. Statistical analysis was performed in SPSS v19, and p < 0.05 was considered to be significant. RESULTS: 432 patients underwent resection of CRLM during this period (67% male; mean age 64.5 years), and of these, 54 (13.5%) had re-resections. The overall 5-year survival in this series was 43% with an actuarial 10-year survival of 40%. A preoperative CEA ≥200 ng/ml was present in 10% of patients and was associated with a poorer 5-year OS (24 vs. 45%; p < 0.001). A positive resection margin <1 mm was present in 16% of patients, and this had a negative impact on 5-year OS (15 vs. 47%; p < 0.001). Tumour differentiation, number, biliary or vascular invasion, size, relationship to primary disease, nodal status of the primary disease or the use of neo-adjuvant chemotherapy had no impact on OS. Multivariate analysis identified only the presence of a positive resection margin (OR 1.75; p < 0.05) and a preoperative CEA ≥200 ng/ml (OR 1.88; p < 0.01) as independent predictors of poor OS. CONCLUSION: Despite the wide variety of prognostic factors reported in the literature, this study was only able to identify a preoperative CEA ≥200 ng/ml and the presence of tumour within 1 mm of the resection margin as being of value in predicting survival. These variables are likely to identify patients who may benefit from intensive follow-up to enable early aggressive treatment of recurrent disease.

Double bypass for inoperable pancreatic malignancy at laparotomy: postoperative complications and long-term outcome.

INTRODUCTION: Between 4% and 13% of patients with operable pancreatic malignancy are found unresectable at the time of surgery. Double bypass is a good option for fit patients but it is associated with a high risk of postoperative complications. The aim of this study was to identify pre-operatively which patients undergoing double bypass are at high risk of complications and to assess their long-term outcome. METHODS: Of the 576 patients undergoing pancreatic resections between 2006 and 2011, 50 patients who underwent a laparotomy for a planned pancreaticoduodenectomy had a double bypass procedure for inoperable disease. Demographic data, risk factors for postoperative complications and pre-operative anaesthetic assessment data including the Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (P-POSSUM) and cardiopulmonary exercise testing (CPET) were collected. RESULTS: Fifty patients (33 men and 17 women) were included in the study. The median patient age was 64 years (range: 39-79 years). The complication rate was 50% and the in-hospital mortality rate was 4%. The P-POSSUM physiology subscore and low anaerobic threshold at CPET were significantly associated with postoperative complications (p =0.005 and p =0.016 respectively) but they were unable to predict them. Overall long-term survival was significantly shorter in patients with postoperative complications (9 vs 18 months). Postoperative complications were independently associated with poorer long-term survival (p =0.003, odds ratio: 3.261). CONCLUSIONS: P-POSSUM and CPET are associated with postoperative complications but the possibility of using them for risk prediction requires further research. However, postoperative complications following double bypass have a significant impact on long-term survival and this type of surgery should therefore only be performed in specialised centres.

Promoter I of the ovine acetyl-CoA carboxylase-alpha gene: an E-box motif at -114 in the proximal promoter binds upstream stimulatory factor (USF)-1 and USF-2 and acts as an insulin-response sequence in differentiating adipocytes.

Acetyl-CoA carboxylase-alpha (ACC-alpha) plays a central role in co-ordinating de novo fatty acid synthesis in animal tissues. We have characterized the regulatory region of the ovine ACC-alpha gene. Three promoters, PI, PII and PIII, are dispersed throughout 50 kb of genomic DNA. Expression from PI is limited to adipose tissue and liver. Sequence comparison of the proximal promoters of ovine and mouse PIs demonstrates high nucleotide identity and that they are characterized by a TATA box at -29, C/EBP (CCAAT enhancer-binding protein)-binding motifs and multiple E-box motifs. A 4.3 kb ovine PI-luciferase reporter construct is insulin-responsive when transfected into differentiated ovine adipocytes, whereas when this construct is transfected into ovine preadipocytes and HepG2 cells the construct is inactive and is not inducible by insulin. By contrast, transfection of a construct corresponding to 132 bp of the proximal promoter linked to a luciferase reporter is active and inducible by insulin in all three cell systems. Insulin signalling to the -132 bp construct in differentiated ovine adipocytes involves, in part, an E-box motif at -114. Upstream stimulatory factor (USF)-1 and USF-2, but not sterol regulatory element-binding protein 1 (SREBP-1), are major components of protein complexes that bind this E-box motif. Activation of the 4.3 kb PI construct in differentiated ovine adipocytes is associated with endogenous expression of PI transcripts throughout differentiation; PI transcripts are not detectable by RNase-protection assay in ovine preadipocytes, HepG2 cells or 3T3-F442A adipocytes. These data indicate the presence of repressor motifs in PI that are required to be de-repressed during adipocyte differentiation to allow induction of the promoter by insulin.

Can biological activity be maintained at ultra-high dilution? An overview of homeopathy, evidence, and Bayesian philosophy.

Forty percent of general practitioners in the Netherlands practice homeopathy. With over 100 homeopathic medical schools, homeopathy is practiced in India along with conventional Western medicine in government clinics. In Britain, 42% of general practitioners refer patients to homeopaths. Two recent meta-analyses of homeopathy both indicate that there is enough evidence to show that homeopathy has added effects over placebo. Against this evidence is a backdrop of considerable scientific scepticism. Homeopathic remedies are diluted substances--some are so diluted that statistically there are no molecules present to explain their proposed biological effects (ultra-high dilutions or UHDs). Without knowledge of the evidence, most scientists would reject UHD effects because of their intrinsic implausibility in the light of our current scientific understanding. The objective of this article is to critically review the major pieces of evidence on UHD effects and suggest how the scientific community should respond to its challenge. Such evidence has been conducted on a diverse range of assays--immunologic, physiological, behavioral, biochemical, and clinical in the form of trials of homeopathic remedies. Evidence of UHD effects has attracted the attention of physicists who have speculated on their physical mechanisms. Included is a critique of several experiments that form the Benveniste affair which was sparked by a publication in Nature that advocated the existence of UHD effects of anti-immunoglobulin E (IgE) on human basophils, and is the paradigm example of how a controversial phenomenon can split the scientific community. It is argued that if the phenomenon was uncontroversial, the evidence suffices to show that UHD effects exist. However, given that the observations contradict well-established theory, normal science has to be abandoned and scientists need to decide for themselves what the likelihood of UHD effects are. Bayesian analysis describes how scientists ought rationally to change their prior beliefs in the light of evidence. Theories by Kuhn and Lakatos indicate that whether UHD effects are proved or not depends on the beliefs and behaviors of scientists in their communities. This article argues that there is as yet insufficient evidence to drive rational scientists to a consensus over UHD effects, even if they possessed knowledge of all the evidence. The difficulty in publishing high-quality UHD research in conventional journals prevents a fair assessment of UHD effects. Given that the existence of UHD effects would revolutionize science and medicine, and given the considerable empirical evidence of them, the philosophies of science tell us that possible UHD effects warrant serious investigation by conventional scientists and serious attention by scientific journals.

Home nebuliser use in children with asthma in two Scottish Health Board Areas.

OBJECTIVE: To audit the use of home nebulisers in children with asthma. DESIGN: Postal questionnaire. SETTING: Two Health Board Areas in Central Scotland--one large industrialised city, one mixed urban and rural. SUBJECTS: 297 children with asthma. MEASURES EVALUATED: Initial supply and technical support for the compressor. EDUCATION: Pattern of drug usage. SYMPTOM CONTROL: Monitoring and treatment of acute attacks. RESULTS: The full burden of the home nebulised therapy is not being met by the NHS. Supply and servicing arrangements for home nebuliser therapy were poorly organised. Chronic asthma symptoms did not appear to be optimally controlled on present medication, with 61% reporting sleep disturbance in the previous three months. About 20% of parents admitted that they would give nebulised bronchodilator therapy more frequently than the recommended 3 to 4 hourly. CONCLUSION: Re-organisation of resources and arrangements could improve the service and bring it in line with recognised standards of care.