Minimally Invasive Surgery for Colorectal Cancer: Benchmarking Uptake for a Regional Improvement Programme.

BACKGROUND: The uptake of minimally invasive surgery (MIS) for patients with colorectal cancer has progressed at differing rates, both across countries, and within countries. This study aimed to investigate uptake for a regional colorectal cancer improvement programme in England. METHOD: We calculated the proportion of patients receiving elective laparoscopic and robot-assisted surgery amongst those diagnosed with colorectal cancer over 3 time periods (2007-2011, 2012-2016 and 2017-2021) in hospitals participating in the Yorkshire Cancer Research Bowel Cancer Improvement Programme (YCR BCIP). These were benchmarked against national rates. Regression analysis and funnel plots were used to develop a data driven approach for analysing trends in the use of MIS at hospitals in the programme. RESULTS: In England, resections performed by MIS increased from 34.9% to 72.9% for colon cancer and from 28.8% to 72.5% for rectal cancer. Robot-assisted surgery increased from 0.1% to 2.7% for colon cancer and from 0.2% to 7.9% for rectal cancer. Wide variation in the uptake of MIS was observed at a hospital level. Detailed analysis of the YCR BCIP region identified a decreasing number of surgical departments, since the start of the programme, as potential outliers for MIS when compared to the English national average. CONCLUSION: Wide variation in use of MIS for colorectal cancer exists within the English National Health Service and a data-driven approach can help identify outlying hospitals. Addressing some of the challenges behind the uptake of MIS, such as ensuring adequate provision of surgical training and equipment, could help increase its use.

Addressing cancer anorexia-cachexia in older patients: Potential therapeutic strategies and molecular pathways.

Cancer cachexia (CC) syndrome, a feature of cancer-associated muscle wasting, is particularly pronounced in older patients, and is characterised by decreased energy intake and upregulated skeletal muscle catabolic pathways. To address CC, appetite stimulants, anabolic drugs, cytokine mediators, essential amino acid supplementation, nutritional counselling, cognitive behavioural therapy, and enteral nutrition have been utilised. However, pharmacological treatments that have also shown promising results, such as megestrol acetate, anamorelin, thalidomide, and delta-9-tetrahydrocannabinol, have been associated with gastrointestinal and cardiovascular complications. Emerging evidence on the efficacy of probiotics in modulating gut microbiota also presents a promising adjunct to traditional therapies, potentially enhancing nutritional absorption and systemic inflammation control. Additionally, low-dose olanzapine has demonstrated improved appetite and weight management in older patients undergoing chemotherapy, offering a potential refinement to current therapeutic approaches. This review aims to elucidate the molecular mechanisms underpinning CC, with a particular focus on the role of anorexia in exacerbating muscle wasting, and to propose pharmacological and non-pharmacological strategies to mitigate this syndrome, particularly emphasising the needs of an older demographic. Future research targeting CC should focus on refining appetite-stimulating drugs with fewer side-effects, specifically catering to the needs of older patients, and investigating nutritional factors that can either enhance appetite or minimise suppression of appetite in individuals with CC, especially within this vulnerable group.

Prerequisites to improve surgical cytoreduction in FIGO stage III/IV epithelial ovarian cancer and subsequent clinical ramifications.

BACKGROUND: No residual disease (CC 0) following cytoreductive surgery is pivotal for the prognosis of women with advanced stage epithelial ovarian cancer (EOC). Improving CC 0 resection rates without increasing morbidity and no delay in subsequent chemotherapy favors a better outcome in these women. Prerequisites to facilitate this surgical paradigm shift and subsequent ramifications need to be addressed. This quality improvement study assessed 559 women with advanced EOC who had cytoreductive surgery between January 2014 and December 2019 in our tertiary referral centre. Following implementation of the Enhanced Recovery After Surgery (ERAS) pathway and prehabilitation protocols, the surgical management paradigm in advanced EOC patients shifted towards maximal surgical effort cytoreduction in 2016. Surgical outcome parameters before, during, and after this paradigm shift were compared. The primary outcome measure was residual disease (RD). The secondary outcome parameters were postoperative morbidity, operative time (OT), length of stay (LOS) and progression-free-survival (PFS). RESULTS: R0 resection rate in patients with advanced EOC increased from 57.3% to 74.4% after the paradigm shift in surgical management whilst peri-operative morbidity and delays in adjuvant chemotherapy were unchanged. The mean OT increased from 133 + 55 min to 197 + 85 min, and postoperative high dependency/intensive care unit (HDU/ICU) admissions increased from 8.1% to 33.1%. The subsequent mean LOS increased from 7.0 + 2.6 to 8.4 + 4.9 days. The median PFS was 33 months. There was no difference for PFS in the three time frames but a trend towards improvement was observed. CONCLUSIONS: Improved CC 0 surgical cytoreduction rates without compromising morbidity in advanced EOC is achievable owing to the right conditions. Maximal effort cytoreductive surgery should solely be carried out in high output tertiary referral centres due to the associated substantial prerequisites and ramifications.

Prospective comparison of two methods for assessing sarcopenia and interobserver agreement on retrospective CT images.

PURPOSE OF THE STUDY: To compare the relationships between two CT derived sarcopenia assessment methods, and compare their relationship with inter-rater and intrarater validations and colorectal surgical outcomes. STUDY DESIGN: 157 CT scans were identified across Leeds Teaching Hospitals National Health Service Trust for patients undergoing colorectal cancer surgery. 107 had body mass index data available, required to determine sarcopenia status. This work explores the relationship between sarcopenia, as measured by both total cross sectional-area (TCSA) and psoas-area (PA) and surgical outcomes. All images were assessed for inter-rater and intrarater variability for both TCSA and PA methods of sarcopenia identification. The raters included a radiologist, an anatomist and two medical students. RESULTS: Prevalence of sarcopenia was different when measured by PA (12.2%-22.4%) in comparison to TCSA (60.8%-70.1%). Strong correlation exists between muscle areas in both TCSA and PA measures, however, there were significant differences between methods after the application of method-specific cut-offs. There was substantial agreement for both intrarater and inter-rater comparisons for both TCSA and PA sarcopenia measures. Outcome data were available for 99/107 patients. Both TCSA and PA have poor association with adverse outcomes following colorectal surgery. CONCLUSIONS: CT-determined sarcopenia can be identified by junior clinicians, those with anatomical understanding and radiologists. Our study identified sarcopenia to have a poor association with adverse surgical outcomes in a colorectal population. Published methods of identifying sarcopenia are not translatable to all clinical populations. Currently available cut-offs require refinement for potential confounding factors, to provide more valuable clinical information.

Recruiting to surgical trials in the emergency setting: using a mixed methods study to understand clinician and patient perspectives.

BACKGROUND: Undertaking randomized clinical trials (RCTs) in emergency surgical settings is associated with methodological and practical challenges. This study explored patients' and clinicians' perspectives associated with the conduct of an RCT comparing laparoscopic and open colorectal surgery in the acute setting. METHODS: All eligible patients screened and enrolled for the 'Laparoscopic versus open colorectal surgery in the acute setting (LaCeS)' multicentre, randomized clinical feasibility trial in five UK NHS Trusts were invited to respond to a survey. Patients and healthcare professionals were also invited to take part in semi-structured interviews. Survey and interviews explored the acceptability of the feasibility trial. Interviews were audio recorded, transcribed verbatim, and analysed using thematic analysis. Survey data were analysed descriptively to assess patient views of the trial and intervention. RESULTS: Out of 72 patients enrolled for the LaCeS RCT, survey data were collected from 28 patients (38.9 per cent), and interviews were conducted with 16 patients and 14 healthcare professionals. Thirteen out of 28 patients (46 per cent) had treatment preferences but these were not strong enough to deter participation. Twelve of the patients interviewed believed that their surgeon preferred laparoscopic surgery, but this did not deter them from participating in the trial. Half of the surgeons interviewed expressed the view that laparoscopic surgery was of benefit in this setting, but recognized that the need for research evidence outweighed their personal treatment preferences. Eight of the 14 recruiters reported that the emergency setting affected recruitment, especially in centres with fewer recruiting surgeons. Interviewees reported that recruitment was helped significantly by using surgical trainees to consent patients. CONCLUSION: This study identified specific challenges for the LaCeS trial design to address and adds significant insights to our understanding of recruiting to emergency surgical trials more broadly.

Differences in the management of patients requiring an emergency resection for colonic cancer in two European populations.

BACKGROUND: Patients with colonic cancer who require emergency colonic cancer surgery often experience poorer outcomes compared with their elective counterparts. In this setting, several treatments approaches are available. In 2009, Danish guidelines recommended treatment with stent for obstruction in left-sided tumours as a bridge to surgery, if expertise is accessible. The aim of this study was to compare the use of elective and emergency resections for colonic cancer and postoperative mortality in two similar demographic populations. METHODS: All patients who underwent a major resection for colonic cancer, between 2005 and 2016 in Denmark and Yorkshire (UK) were identified. The proportion undergoing emergency surgery, the proportion receiving a stent procedure before their resection, and 30-day postoperative mortality were compared between the populations. Logistic regression was used to determine changes in the proportion of those undergoing emergency surgery and 30-day postoperative mortality. RESULTS: Out of 45 397 patients treated during the study interval, 41 880 were selected. Emergency surgery decreased in Denmark from 16.6 per cent in 2005-07 to 12.9 per cent in 2014-16, but increased in Yorkshire (13.5 per cent to 16.8 per cent). Danish patients with left-sided tumours were less likely to undergo emergency surgery (risk ratio 0.90, 95 per cent c.i. 0.82 to 0.99) and an increase in stent use coincided with a statistically significant decrease in emergency surgery in these patients. Thirty-day postoperative mortality in all resections (elective and emergency) decreased in both populations, but a larger decrease was observed in Denmark (7.7 per cent to 3.0 per cent in Denmark and 7.1 per cent to 3.3 per cent in Yorkshire). CONCLUSION: Patients in Denmark experienced a reduction in the use of emergency resection and increase in stenting procedures, following the policy implemented in some departments of converting potential emergency resections into elective resections.

Usability of myfood24 Healthcare and Mathematical Diet Optimisation in Clinical Populations: A Pilot Feasibility Randomised Controlled Trial.

Monitoring nutritional intake is of clinical value, but few existing tools offer electronic dietary recording, instant nutritional analysis, and a platform connecting healthcare teams with patients that provides timely, personalised support. This feasibility randomised controlled trial tests the usability of 'myfood24 Healthcare', a dietary assessment app and healthcare professional website, in two clinical populations. Patients were recruited from a weight management programme (n21) and from a group of gastroenterology surgery outpatients (n = 27). They were randomised into three groups: standard care, myfood24, or myfood24 + diet optimisation (automated suggestions for dietary improvement). The participants were asked to record their diet at least four times over eight weeks. During the study, healthcare professionals viewed recorded dietary information to facilitate discussions about diet and nutritional targets. The participants provided feedback on usability and acceptability. A total of 48 patients were recruited, and 16 were randomised to each of the three groups. Compliance among app users (n = 32) was reasonable, with 25 (78%) using it at least once and 16 (50%) recording intake for four days or more. Among users, the mean (standard deviation) number of days used was 14.0 (17.5), and the median (interquartile range) was six (2.5-17.0) over 2 months. Feedback questionnaires were completed by only 23 of 46 participants (50%). The mean System Usability Score (n = 16) was 59 (95% confidence interval, 48-70). Patient and healthcare professional feedback indicates a need for more user training and the improvement of some key app features such as the food search function. This feasibility study shows that myfood24 Healthcare is acceptable for patients and healthcare professionals. These data will inform app refinements and its application in a larger clinical effectiveness trial.

Collection of cancer Patient Reported Outcome Measures (PROMS) to link with primary and secondary electronic care records to understand and improve long term cancer outcomes: A protocol paper.

INTRODUCTION: More people are living with and beyond a cancer diagnosis. There is limited understanding of the long-term effects of cancer and cancer treatment on quality of life and personal and household finances when compared to people without cancer. In a separate protocol we have proposed to link de-identified data from electronic primary care and hospital records for a large population of cancer survivors and matched controls. In this current protocol, we propose the linkage of Patient Reported Outcomes Measures data to the above data for a subset of this population. The aim of this study is to investigate the full impact of living with and beyond a cancer diagnosis compared to age and gender matched controls. A secondary aim is to test the feasibility of the collection of Patient Reported Outcomes Measures (PROMS) data and the linkage procedures of the PROMs data to electronic health records data. MATERIALS AND METHODS: This is a cross-sectional study, aiming to recruit participants treated at the Leeds Teaching Hospitals National Health Service Trust. Eligible patients will be cancer survivors at around 5 years post-diagnosis (breast, colorectal and ovarian cancer) and non-cancer patient matched controls attending dermatology out-patient clinics. They will be identified by running a query on the Leeds Teaching Hospitals Trust patient records system. Approximately 6000 patients (2000 cases and 4000 controls) will be invited to participate via post. Participants will be invited to complete PROMs assessing factors such as quality of life and finances, which can be completed on paper or online (surveys includes established instruments, and bespoke instruments (demographics, financial costs). This PROMs data will then be linked to routinely collected de-identified data from patient's electronic primary care and hospital records. DISCUSSION: This innovative work aims to create a truly 'comprehensive patient record' to provide a broad picture of what happens to cancer patients across their cancer pathway, and the long-term impact of cancer treatment. Comparisons can be made between the cases and controls, to identify the aspects of life that has had the greatest impact following a cancer diagnosis. The feasibility of linking PROMs data to electronic health records can also be assessed. This work can inform future support offered to people living with and beyond a cancer diagnosis, clinical practice, and future research methodologies.

Symptomatic resolution of malignant bowel obstruction by endoscopic catheterisation of an enterocutaneous fistula.

Patients with advanced intra-abdominal malignancy frequently experience nausea and vomiting, however these symptoms can be difficult to manage. A woman in her seventies with high grade primary peritoneal adenocarcinoma developed intermittent small bowel obstruction following extensive surgery. Poor relief was provided by pharmacological approaches and nasogastric tube insertion. Further surgical management was deemed unsuitable due to the significant possibility of complications and likely impairment of the patient's quality of life. A conservative approach was used by using a novel therapeutic intervention: an endoscope was used to visualise an enterocutaneous fistula tract proximal to the obstruction and a gastrostomy catheter was fluoroscopically inserted. This maintained fistula tract patency, permitting drainage of bowel contents and therefore resolving the patient's symptoms. We therefore describe a novel therapeutic approach where endoscopic insertion of a gastrostomy catheter maintained patency of an enterocutaneous fistula, enabling lasting relief of bowel obstruction in a manner acceptable to the patient.

Prevalence of frailty and reliability of established frailty instruments in adult elective colorectal surgical patients: a prospective cohort study.

PURPOSE: Large population studies now demonstrate that frailty is prevalent in all adult age groups. Limited data exist on the association between frailty and surgical outcome in younger patients. The aim of the study was to explore the agreement between frailty identification tools and collect pilot data on their predictive value for frailty-associated outcomes in an adult surgical population. STUDY DESIGN: Prospective cohort study. RESULTS: Frailty scores were recorded in 200 patients (91 men), mean (range) age 57 (18-92) years. The prevalence of prefrailty was 52%-67% and that of frailty 2%-32% depending on the instrument used. Agreement between the instruments was poor, kappa 0.08-0.17 in pairwise comparisons. Outcome data were available on 160 patients. Only the frailty phenotype was significantly associated with adverse outcomes, RR 6.1 (1.5-24.5) for postoperative complications. The three frailty scoring instruments studies had good sensitivity (Clinical Frailty Scale (CFS)-90%, Accumulation Deficit (AD)-96%, Frailty Phenotype (FP)-97%) but poor specificity (CFS-12%, AD-13%, FP-18%) for the prediction of postoperative complications. All three instruments were poorly predictive of adverse outcomes with likelihood ratios of CFS-1.02, AD-1.09 and FP-1.17. CONCLUSIONS: This study showed a significant prevalence of prefrailty and frailty in adult colorectal surgical patients of all ages. There was poor agreement between three established frailty scoring instruments. Our data do not support the use of current frailty scoring instruments in all adult colorectal surgical patients. However, the significant prevalence of prefrailty and frailty across all age groups of adult surgical patient justifies further research to refine frailty scoring in surgical patients.

Influence of age on surgical treatment and postoperative outcomes of patients with colorectal cancer in Denmark and Yorkshire, England.

AIM: Denmark and Yorkshire are demographically similar and both have undergone changes in their management of colorectal cancer to improve outcomes. The differential provision of surgical treatment, especially in the older age groups, may contribute to the magnitude of improved survival rates. This study aimed to identify differences in the management of colorectal cancer surgery and postoperative outcomes according to patient age between Denmark and Yorkshire. METHOD: This was a retrospective population-based study of colorectal cancer patients diagnosed in Denmark and Yorkshire between 2005 and 2016. Proportions of patients undergoing major surgical resection, postoperative mortality and relative survival were compared between Denmark and Yorkshire across several age groups (18-59, 60-69, 70-79 and ≥80 years) and over time. RESULTS: The use of major surgical resection was higher in Denmark than in Yorkshire, especially for patients aged ≥80 years (70.5% versus 50.5% for colon cancer, 49.3% versus 38.1% for rectal cancer). Thirty-day postoperative mortality for Danish patients aged ≥80 years was significantly higher than that for Yorkshire patients with colonic cancer [OR (95% CI) = 1.22 (1.07, 1.38)] but not for rectal cancer or for 1-year postoperative mortality. Relative survival significantly increased in all patients aged ≥80 years except for Yorkshire patients with colonic cancer. CONCLUSION: This study suggests that there are major differences between the management of elderly patients with colorectal cancer between the two populations. Improved selection for surgery and better peri- and postoperative care in these patients appears to improve long-term outcomes, but may come at the cost of a higher 30-day mortality.

The CABI Trial: an Unblinded Parallel Group Randomised Controlled Feasibility Trial of Long-Course Antibiotic Therapy (28 Days) Compared with Short Course (≤ 10 Days) in the Prevention of Relapse in Adults Treated for Complicated Intra-Abdominal Infection.

PURPOSE: Relapse after complicated intra-abdominal infection (cIAI) remains common after treatment. The optimal antibiotic treatment duration for cIAIs is uncertain, especially in cases where source control is not achieved. We hypothesised that in patients with cIAIs, regardless of source control intervention, there would be a lower relapse rate with long-course antibiotics (28 days) compared with short course (≤ 10 days). We piloted a trial comparing ≤ 10-day with 28-day antibiotic treatment for cIAI. METHODS: A randomised controlled unblinded feasibility trial was conducted. Eligible participants were adult patients with a cIAI that were diagnosed ≤ 6 days prior to screening. Randomisation was to long-course (28 days) or short-course (≤10 days) antibiotic therapy. Choice of antibiotics was determined by the clinical team. Participants were followed up for 90 days. Primary outcomes were willingness of participants to be randomised and feasibility of trial procedures. RESULTS: In total, 172 patients were screened, 84/172 (48.8%) were eligible, and 31/84 (36.9%) were randomised. Patients were assigned to either the short-course arm (18/31, 58.0%) or the long-course arm (13/31, 41.9%). One patient in the short-course arm withdrew after randomisation. In the short-course arm, 4/17 (23.5%) were treated for a cIAI relapse vs 0/13 (0.0%) relapses in the long-course arm. Protocol violations included deviations from protocol-assigned antibiotic duration and interruptions to antibiotic therapy. CONCLUSIONS: This feasibility study identified opportunities to increase recruitment in a full trial. This study demonstrates completion of a randomised controlled trial to further evaluate if the optimum antibiotic duration for cIAIs is feasible. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03265834.

The hidden cost of catheter related blood stream infections in patients on parenteral nutrition.

BACKGROUND & AIMS: Parenteral nutrition (PN) is a valuable and life-saving treatment for patients with intestinal failure. While its use is increasing, it has been demonstrated to be a risk factor for intravenous catheter-related blood stream infection (CRBSI) - a significant, serious and potentially fatal complication of PN use. CRBSI can have serious secondary consequences for patients, though, there is a paucity of literature describing these. The aim of this study is to audit the incidence of, and evaluate the consequences of, complications associated with CRBSI. METHODS: Medical records were examined for all parenterally fed patients diagnosed with a CRBSI from 01/01/16 to 31/12/17 in a UK tertiary referral centre for patients requiring intravenous nutritional support. Patients were identified prospectively; data relating to the infection and complications was collected retrospectively. RESULTS: 114 episodes of CRBSI were recorded in 80 patients. 57 occurred during an inpatient admission, 57 occurred in the community and resulted in admission. 21 different adverse events occurred as a result of the CRBSI. The complications identified were varied with the most common being acute kidney injury, deranged electrolytes and urinary tract infections. Other significant complications included DVT, pulmonary abscess and infective endocarditis. 35% of episodes resulted in delayed discharge and 12% required escalation to a critical care bed. The financial impact is estimated at over £800,000 per annum. CONCLUSIONS: The findings demonstrate a plethora of complications which can arise following CRBSI, which pose a significant health risk to parenterally fed patients who already have reduced physiological reserve. Moreover, these findings represent additional financial and resource burden to the health service. The adverse events resulting from CRBSIs should, therefore, be audited to improve outcomes: well-resourced specialist centres are best placed to provide this service.

Optimal management of malignant left-sided large bowel obstruction: do international guidelines agree?

Background: Approximately 20% of patients diagnosed with colorectal cancer will present with left-sided large bowel obstruction. The optimal management of this cohort of patients remains unclear. We aimed to review international guidelines to see if there was a consensus on the treatment of this surgical emergency. Methods: The PubMed and Medline databases were searched for guidelines on the management of left-sided, malignant large bowel obstruction (MBO) between 2010 and 2018. Results: Nineteen guidelines were identified spanning a range of continents. There was no clear consensus on the management of potentially resectable disease. Eight guidelines (42%) suggested primary surgery, two guidelines (11%) suggested stenting as a bridge to surgery and nine guidelines (47%) suggested surgery or stenting could be performed. Primary resection with or without anastomosis was the most frequently recommended procedure (n = 6 35%), but over a third of guidelines gave no operative recommendations. There was very limited detail on the stenting procedure and how long elective surgery should be deferred. In the palliative situation, there was general agreement that stents should be offered in preference to surgery. Conclusion: International guidelines offer limited and contrasting recommendations on the management of left-sided MBO. There is a lack of high-quality evidence to support whether emergency surgery or stenting as a bridge to surgery is the optimal procedure in terms of morbidity, mortality and long-term oncological outcome.

Colo-Pro: a pilot randomised controlled trial to compare standard bolus-dosed cefuroxime prophylaxis to bolus-continuous infusion-dosed cefuroxime prophylaxis for the prevention of infections after colorectal surgery.

Standard bolus-dosed antibiotic prophylaxis may not inhibit growth of antibiotic resistant colonic bacteria, a cause of SSIs after colorectal surgery. An alternative strategy is continuous administration of antibiotic throughout surgery, maintaining concentrations of antibiotics that inhibit growth of resistant bacteria. This study is a pilot comparing bolus-continuous infusion with bolus-dosed cefuroxime prophylaxis in colorectal surgery. This is a pilot randomised controlled trial in which participants received cefuroxime bolus-infusion (intervention arm) targeting free serum cefuroxime concentrations of 64 mg/L, or 1.5 g cefuroxime as a bolus dose four-hourly (standard arm). Patients in both arms received metronidazole (500 mg intravenously). Eligible participants were adults undergoing colorectal surgery expected to last for over 2 h. Results were analysed on an intention-to-treat basis. The study was successfully piloted, with 46% (90/196) of eligible patients recruited and 89% (80/90) of participants completing all components of the protocol. A trialled bolus-continuous dosing regimen was successful in maintaining free serum cefuroxime concentrations of 64 mg/L. No serious adverse reactions were identified. Rates of SSIs (superficial and deep SSIs) were lower in the intervention arm than the standard treatment arm (24% (10/42) vs. 30% (13/43)), as were infection within 30 days of operation (41% (17/43) vs 51% (22/43)) and urinary tract infections (2% (1/42) vs. 9% (4/43)). These infection rates can be used to power future clinical trials. This study demonstrates the feasibility of cefuroxime bolus-continuous infusion of antibiotic prophylaxis trials, and provides safety data for infusions targeting free serum cefuroxime concentrations of 64 mg/L. Trial registration: NCT02445859 .

Feasibility of a multicentre, randomised controlled trial of laparoscopic versus open colorectal surgery in the acute setting: the LaCeS feasibility trial protocol.

INTRODUCTION: Acute colorectal surgery forms a significant proportion of emergency admissions within the National Health Service. There is limited evidence to suggest minimally invasive surgery may be associated with improved clinical outcomes in this cohort of patients. Consequently, there is a need to assess the clinical effectiveness and cost-effectiveness of laparoscopic surgery in the acute colorectal setting. However,emergency colorectal surgical trials have previously been difficult to conduct due to issues surrounding recruitment and equipoise. The LaCeS (randomised controlled trial of Laparoscopic versus open Colorectal Surgery in the acute setting) feasibility trial will determine the feasibility of conducting a definitive, phase III trial of laparoscopic versus open acute colorectal resection. METHODS AND ANALYSIS: The LaCeS feasibility trial is a prospective, multicentre, single-blinded, parallel group, pragmatic randomised controlled feasibility trial. Patients will be randomised on a 1:1 basis to receive eitherlaparoscopic or open surgery. The trial aims to recruit at least 66 patients from five acute general surgical units across the UK. Patients over the age of 18 with a diagnosis of acute colorectal pathology requiring resection on clinical and radiological/endoscopic investigations, with a National Confidential Enquiry into Patient Outcome and Death classification of urgent will be considered eligible for participation. The primary outcome is recruitment. Secondary outcomes include assessing the safety profile of laparoscopic surgery using intraoperative and postoperative complication rates, conversion rates and patient-safety indicators as surrogate markers. Clinical and patient-reported outcomes will also be reported. The trial will contain an embedded qualitative study to assess clinician and patient acceptability of trial processes. ETHICS AND DISSEMINATION: The LaCeS feasibility trial is approved by the Yorkshire and The Humber, Bradford Leeds Research Ethics Committee (REC reference: 15/ YH/0542). The results from the trial will be presented at national and international colorectal conferences and will be submitted for publication to peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN15681041; Pre-results.

AZD1775 induces toxicity through double-stranded DNA breaks independently of chemotherapeutic agents in p53-mutated colorectal cancer cells.

AZD1775 is a small molecule WEE1 inhibitor used in combination with DNA-damaging agents to cause premature mitosis and cell death in p53-mutated cancer cells. Here we sought to determine the mechanism of action of AZD1775 in combination with chemotherapeutic agents in light of recent findings that AZD1775 can cause double-stranded DNA (DS-DNA) breaks. AZD1775 significantly improved the cytotoxicity of 5-FU in a p53-mutated colorectal cancer cell line (HT29 cells), decreasing the IC50 from 9.3 µM to 3.5 µM. Flow cytometry showed a significant increase in the mitotic marker pHH3 (3.4% vs. 56.2%) and DS-DNA break marker γH2AX (5.1% vs. 50.7%) for combination therapy compared with 5-FU alone. Combination therapy also increased the amount of caspase-3 dependent apoptosis compared with 5-FU alone (4% vs. 13%). The addition of exogenous nucleosides to combination therapy significantly rescued the increased DS-DNA breaks and caspase-3 dependent apoptosis almost to the levels of 5-FU monotherapy. In conclusion, AZD1775 enhances 5-FU cytotoxicity through increased DS-DNA breaks, not premature mitosis, in p53-mutated colorectal cancer cells. This finding is important for designers of future clinical trials when considering the optimal timing and duration of AZD1775 treatment.

Upregulated WEE1 protects endothelial cells of colorectal cancer liver metastases.

Surgical resection of colorectal cancer liver metastases (CLM) can be curative, yet 80% of patients are unsuitable for this treatment. As angiogenesis is a determinant of CLM progression we isolated endothelial cells from CLM and sought a mechanism which is upregulated, essential for angiogenic properties of these cells and relevant to emerging therapeutic options. Matched CLM endothelial cells (CLMECs) and endothelial cells of normal adjacent liver (LiECs) were superficially similar but transcriptome sequencing revealed molecular differences, one of which was unexpected upregulation and functional significance of the checkpoint kinase WEE1. Western blotting confirmed that WEE1 protein was upregulated in CLMECs. Knockdown of WEE1 by targeted short interfering RNA or the WEE1 inhibitor AZD1775 suppressed proliferation and migration of CLMECs. Investigation of the underlying mechanism suggested induction of double-stranded DNA breaks due to nucleotide shortage which then led to caspase 3-dependent apoptosis. The implication for CLMEC tube formation was striking with AZD1775 inhibiting tube branch points by 83%. WEE1 inhibitors might therefore be a therapeutic option for CLM and could be considered more broadly as anti-angiogenic agents in cancer treatment.

Accuracy of the Surgeons' Clinical Prediction of Postoperative Major Complications Using a Visual Analog Scale.

BACKGROUND: Although the risk factors that contribute to postoperative complications are well recognized, prediction in the context of a particular patient is more difficult. We were interested in using a visual analog scale (VAS) to capture surgeons' prediction of the risk of a major complication and to examine whether this could be improved. METHODS: The study was performed in 3 stages. In phase I, the surgeon assessed the risk of a major complication on a 100-mm VAS immediately before and after surgery. A quality control questionnaire was designed to check if the VAS was being scored as a linear scale. In phase II, a VAS with 6 subscales for different areas of clinical risk was introduced. In phase III, predictions were completed following the presentation of detailed feedback on the accuracy of prediction of complications. RESULTS: In total, 1295 predictions were made by 58 surgeons in 859 patients. Eight surgeons did not use a linear scale (6 logarithmic, 2 used 4 categories of risk). Surgeons made a meaningful prediction of major complications (preoperative median score 40 mm for complications v. 22 mm for no complication, P < 0.001; postoperative 46 mm v. 21 mm, P < 0.001). In phase I, the discrimination of prediction for preoperative (0.778), postoperative (0.810), and POSSUM (Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity) morbidity (0.750) prediction was similar. Although there was no improvement in prediction with a multidimensional VAS, there was a significant improvement in the discrimination of prediction after feedback (preoperative, 0.895; postoperative, 0.918). CONCLUSION: Awareness of different ways a VAS is scored is important when designing and interpreting studies. Clinical assessment of major complications by the surgeon was initially comparable to the prediction of the POSSUM morbidity score and improved significantly following the presentation of clinically relevant feedback.