A systematic methodology review of fluorescence-guided cancer surgery to inform the development of a core master protocol and outcome set.

BACKGROUND: Fluorescence-guided precision cancer surgery may improve survival and minimize patient morbidity. Efficient development of promising interventions is however hindered by a lack of common methodology. This methodology review aimed to synthesize descriptions of technique, governance processes, surgical learning and outcome reporting in studies of fluorescence-guided cancer surgery to provide guidance for the harmonized design of future studies. METHODS: A systematic search of MEDLINE, EMBASE and CENTRAL databases from 2016-2020 identified studies of all designs describing the use of fluorescence in cancer surgery. Dual screening and data extraction was conducted by two independent teams. RESULTS: Of 13,108 screened articles, 426 full text articles were included. The number of publications per year increased from 66 in 2016 to 115 in 2020. Indocyanine green was the most commonly used fluorescence agent (391, 91.8%). The most common reported purpose of fluorescence guided surgery was for lymph node mapping (195, 5%) and non-specific tumour visualization (94, 2%). Reporting about surgical learning and governance processes incomplete. A total of 2,577 verbatim outcomes were identified, with the commonly reported outcome lymph node detection (796, 30%). Measures of recurrence (32, 1.2%), change in operative plan (23, 0.9%), health economics (2, 0.1%), learning curve (2, 0.1%) and quality of life (2, 0.1%) were rarely reported. CONCLUSION: There was evidence of methodological heterogeneity that may hinder efficient evaluation of fluorescence surgery. Harmonization of the design of future studies may streamline innovation.

Outcomes of colorectal cancer resection in patients with inflammatory bowel disease: a national population-based analysis in England and Wales.

AIM: The aim was to compare early postoperative outcomes and 2-year cancer-specific mortality following colorectal cancer (CRC) resection in patients with and without inflammatory bowel disease (IBD) in England and Wales. METHOD: Records for patients in the National Bowel Cancer Audit who had major CRC resection between April 2014 and December 2017 were linked to routinely collected hospital level administrative datasets and chemotherapy and radiotherapy datasets. Multivariable regression models were used to compare outcomes with adjustment for patient and tumour characteristics. RESULTS: In all, 63 365 patients were included. 1285 (2.0%) had an IBD diagnosis: 839 (65.3%) ulcerative colitis, 435 (33.9%) Crohn's disease and 11 (0.9%) were indeterminate. IBD patients were younger, had more advanced cancer staging and a higher proportion of right-sided tumours. They also had a higher proportion of emergency resection, total/subtotal colectomy, open surgery and stoma formation at resection, with longer hospital admissions and higher rates of unplanned readmission and reoperation. Fewer rectal cancer patients with IBD received neoadjuvant radiotherapy (24.8% vs. 36.0%, P = 0.005) whilst similar proportions of Stage III colon cancer patients received adjuvant chemotherapy. Ninety-day postoperative mortality was similar, but unadjusted 2-year cancer-specific mortality was significantly higher in patients with IBD (subdistribution hazard ratio 1.35, 95% CI 1.18-1.55). Risk adjustment for patient and tumour factors reduced this association (adjusted subdistribution hazard ratio 1.22, 95% CI 1.05-1.43). CONCLUSION: Patients with IBD and CRC are a distinct patient group who develop CRC at a younger age and undergo more radical surgery. They have worse cancer survival, with the difference in prognosis appearing after the early postoperative period.

Role of Emergency Laparoscopic Colectomy for Colorectal Cancer: A Population-based Study in England.

OBJECTIVE: To evaluate factors associated with the use of laparoscopic surgery and the associated postoperative outcomes for urgent or emergency resection of colorectal cancer in the English National Health Service. SUMMARY OF BACKGROUND DATA: Laparoscopy is increasingly used for elective colorectal cancer surgery, but uptake has been limited in the emergency setting. METHODS: Patients recorded in the National Bowel Cancer Audit who underwent urgent or emergency colorectal cancer resection between April 2010 and March 2016 were included. A multivariable multilevel logistic regression model was used to estimate odds ratios (ORs) of undergoing laparoscopic resection and postoperative outcome according to approach. RESULTS: There were 15,516 patients included. Laparoscopy use doubled from 15.1% in 2010 to 30.2% in 2016. Laparoscopy was less common in patients with poorer physical status [American Society of Anaesthesiologists (ASA) 4/5 vs 1, OR 0.29 (95% confidence interval, 95% CI 0.23-0.37), P < 0.001] and more advanced T-stage [T4 vs T0-T2, OR 0.28 (0.23-0.34), P < 0.001] and M-stage [M1 vs M0, OR 0.85 (0.75-0.96), P < 0.001]. Age, socioeconomic deprivation, nodal stage, hospital volume, and a dedicated colorectal emergency service were not associated with laparoscopy. Laparoscopic patients had a shorter length of stay [median 8 days (interquartile range (IQR) 5 to 15) vs 12 (IQR 8 to 21), adjusted mean difference -3.67 (-4.60 to 2.74), P < 0.001], and lower 90-day mortality [8.1% vs 13.0%; adjusted OR 0.78 (0.66-0.91), P = 0.004] than patients undergoing open resection. There was no significant difference in rates of readmission or reoperation by approach. CONCLUSION: The use of laparoscopic approach in the emergency resection of colorectal cancer is linked to a shorter length of hospital stay and reduced postoperative mortality.

The impact of advancing age on incidence of hepatectomy and post-operative outcomes in patients with colorectal cancer liver metastases: a population-based cohort study.

BACKGROUND: Clinical outcomes for elderly patients undergoing liver resection for colorectal cancer (CRC) liver metastases are poorly characterised. This study aimed to investigate the impact of advancing age on the incidence of liver resection and post-operative outcomes. METHODS: Patients in the National Bowel Cancer Audit undergoing major CRC resection from 2010 to 2016 in England were included. Liver resection was identified from linked Hospital Episode Statistics data. A Cox-proportional hazards model was used to compare 3-year mortality. RESULTS: Of 117,005 patients, 6081 underwent liver resection. For patients <65 years there was 1 liver resection per 12 cases, 65-74, 1 per 17, and ≥75, 1 per 40. 90-day mortality after liver resection increased with advancing age (<65 0.9% (26/2829), 65-74 2.8% (57/2070), ≥75 4.0% (47/1182); P < 0.001). Age was an independent risk factor for 3-year mortality. Patients 65-74 did not have adjusted mortality higher than those <65, yet age ≥75 was associated with increased overall mortality (Hazard ratio (HR) 1.47 (95% CI 1.30-1.68)) and cancer-specific mortality (HR 1.30 (95% CI 1.13-1.49)). CONCLUSION: Although advancing age was associated with higher rates of 90-day mortality following liver resection, 3-year mortality for patients 65-74 years was comparable to younger patients. These results will aid clinicians and patients in pre-operative decision-making.

Calculating the risk of a pancreatic fistula after a pancreaticoduodenectomy: a systematic review.

BACKGROUND: A post-operative pancreatic fistula (POPF) is a major cause of morbidity and mortality after a pancreaticoduodenectomy (PD). This systematic review aimed to identify all scoring systems to predict POPF after a PD, consider their clinical applicability and assess the study quality. METHOD: An electronic search was performed of Medline (1946-2014) and EMBASE (1996-2014) databases. Results were screened according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and quality assessed according to the QUIPS (quality in prognostic studies) tool. RESULTS: Six eligible scoring systems were identified. Five studies used the International Study Group on Pancreatic Fistula (ISGPF) definition. The proposed scores feature between two and five variables and of the 16 total variables, the majority (12) featured in only one score. Three scores could be fully completed pre-operatively whereas 1 score included intra-operative and two studies post-operative variables. Four scores were internally validated and of these, two scores have been subject to subsequent multicentre review. The median QUIPS score was 38 out of 50 (range 16-50). CONCLUSION: These scores show potential in calculating the individualized patient risk of POPF. There is, however, much variation in current scoring systems and further validation in large multicentre cohorts is now needed.

The Perioperative Quality Improvement Programme (PQIP patient study): protocol for a UK multicentre, prospective cohort study to measure quality of care and outcomes after major surgery.

INTRODUCTION: Major surgery accounts for a substantial proportion of health service activity, due not only to the primary procedure, but the longer-term health implications of poor short-term outcome. Data from small studies or from outside the UK indicate that rates of complications and failure to rescue vary between hospitals, as does compliance with best practice processes. Within the UK, there is currently no system for monitoring postoperative complications (other than short-term mortality) in major non-cardiac surgery. Further, there is variation between national audit programmes, in the emphasis placed on quality assurance versus quality improvement, and therefore the principles of measurement and reporting which are used to design such programmes. METHODS AND ANALYSIS: The PQIP patient study is a multi-centre prospective cohort study which recruits patients undergoing major surgery. Patient provide informed consent and contribute baseline and outcome data from their perspective using a suite of patient-reported outcome tools. Research and clinical staff complete data on patient risk factors and outcomes in-hospital, including two measures of complications. Longer-term outcome data are collected through patient feedback and linkage to national administrative datasets (mortality and readmissions). As well as providing a uniquely granular dataset for research, PQIP provides feedback to participating sites on their compliance with evidence-based processes and their patients' outcomes, with the aim of supporting local quality improvement. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Health Research Authority in the UK. Dissemination of interim findings (non-inferential) will form a part of the improvement methodology and will be provided to participating centres at regular intervals, including near-real time feedback of key process measures. Inferential analyses will be published in the peer-reviewed literature, supported by a comprehensive multi-modal communications strategy including to patients, policy makers and academic audiences as well as clinicians.

Protocol for a multicentre, dual prospective and retrospective cohort study investigating timing of ileostomy closure after anterior resection for rectal cancer: The CLOSurE of Ileostomy Timing (CLOSE-IT) study.

INTRODUCTION: A defunctioning ileostomy is often formed during rectal cancer surgery to reduce the potentially fatal sequelae of anastomotic leak. Once the ileostomy is closed and bowel continuity restored, many patients can suffer poor bowel function, that is, low anterior resection syndrome (LARS). It has been suggested that delay to closure can increase incidence of LARS which is known to significantly reduce quality of life. Despite this, within the UK, time to closure of ileostomy is not subject to national targets within the National Health Service and delay to closure exceeds 18 months in one-third of patients. Clinical factors, surgeon and patient preference or service pressures may all impact time to closure, yet to date no study has investigated this. The aim of this UK-wide study is to assess time to ileostomy closure and identify reasons for delays. METHODS AND ANALYSIS: A UK-wide multicentre prospective snapshot study, together with retrospective analysis of ileostomy closure through The Dukes' Club Research Collaborative including patients undergoing ileostomy closure in a 3-month period (April to June 2018) and all patients who underwent anterior resection and ileostomy formation over a historical 12-month period (2015). Time to closure and incidence of 'non-closure' will be calculated. Units will be surveyed to determine local clinical and management protocols and barriers to timely closure. Multivariate linear regression analysis will be used to determine factors significantly associated with delay to ileostomy closure. ETHICS AND DISSEMINATION: Study approved by the South West-Exeter Research Ethics Committee and the Health Research Authority. Study results will be submitted for presentation at international conferences and for publication in peer-reviewed journals. Results will be presented to and discussed with the patient and public representatives and relevant national bodies to facilitate the development of consensus guidelines on optimum treatment pathways.

Effect of public reporting of surgeons' outcomes on patient selection, "gaming," and mortality in colorectal cancer surgery in England: population based cohort study.

OBJECTIVE: To determine the effect of surgeon specific outcome reporting in colorectal cancer surgery on risk averse clinical practice, "gaming" of clinical data, and 90 day postoperative mortality. DESIGN: National cohort study. SETTING: English National Health Service hospital trusts. POPULATION: 111 431 patients diagnosed as having colorectal cancer from 1 April 2011 to 31 March 2015 included in the National Bowel Cancer Audit. INTERVENTION: Public reporting of surgeon specific 90 day mortality in elective colorectal cancer surgery in England introduced in June 2013. MAIN OUTCOME MEASURES: Proportion of patients with colorectal cancer who had an elective major resection, predicted 90 day mortality based on characteristics of patients and tumours, and observed 90 day mortality adjusted for differences in characteristics of patients and tumours, comparing patients who had surgery between April 2011 and June 2013 and between July 2013 and March 2015. RESULTS: The proportion of patients with colorectal cancer undergoing major resection did not change after the introduction of surgeon specific public outcome reporting (39 792/62 854 (63.3%) before versus 30 706/48 577 (63.2%) after; P=0.8). The proportion of these major resections categorised as elective or scheduled also did not change (33 638/39 792 (84.5%) before versus 25 905/30 706 (84.4%) after; P=0.5). The predicted 90 day mortality remained the same (2.7% v 2.7%; P=0.3), but the observed 90 day mortality fell (952/33 638 (2.8%) v 552/25 905 (2.1%)). Change point analysis showed that this reduction was over and above the existing downward trend in mortality before the introduction of public outcome reporting (P=0.03). CONCLUSIONS: This study did not find evidence that the introduction of public reporting of surgeon specific 90 day postoperative mortality in elective colorectal cancer surgery has led to risk averse clinical practice behaviour or "gaming" of data. However, its introduction coincided with a significant reduction in 90 day mortality.

Posterior Superior Mesenteric Artery First Dissection Versus Classical Approach in Pancreaticoduodenectomy: Outcomes of a Case-Matched Study.

OBJECTIVES: Posterior superior mesenteric artery (SMA) first dissection in pancreaticoduodenectomy (PD) may allow for early assessment of resectability and aberrant anatomy. Study objectives were to compare resection margins, perioperative outcomes, disease-free survival (DFS) and overall survival (OS) in patients undergoing a posterior SMA first dissection PD to a classical technique PD. METHODS: Patients (n = 77) who underwent a posterior SMA first PD for adenocarcinoma were case matched for patient and tumor characteristics with patients undergoing a classical approach PD from 2006 to 2014 (n = 177). RESULTS: The SMA first patients had an improved negative resection margin rate (27 [35.1%] vs 14 [18.2%], P = 0.042) and a higher lymph node yield (median 28 [22-34] vs 21 [17-27], P < 0.001) compared with the classical approach group. No difference was demonstrated in serious complications or 30-day mortality between the SMA first and classical approach patients (Clavien-Dindo 3/4 16 [20.8%] vs 11 [14.3%], P = 0.336; 30-day mortality 3 [3.9%] vs 3 [3.9%], P = 1.00 respectively). Median DFS and OS was similar in SMA first compared with classical approach patients (DFS, 1.6 vs 1.1 years, P = 0.122; OS, 2.5 vs 1.5 years, P = 0.220 respectively). CONCLUSIONS: A posterior SMA first approach is a comparably safe technique that may improve oncological results in PD compared with classical approach dissection.

Sustained Isoprostane E2 Elevation, Inflammation and Fibrosis after Acute Ischaemia-Reperfusion Injury Are Reduced by Pregnane X Receptor Activation.

Liver grafts donated after cardiac death are increasingly used to expand the donor pool but are prone to ischaemic-type biliary lesions. The anti-inflammatory effects of the activated pregnane X receptor have previously been shown to be beneficial in a number of inflammatory liver conditions. However, its role in reducing peri-portal inflammation and fibrosis following ischaemia-reperfusion injury has not been investigated. Hepatic injury and its response to pregnane X receptor activation was examined after partial hepatic ischaemia-reperfusion injury induced by surgically clamping the left and middle lobar blood vessels in rats. Molecular and pathological changes in the liver were examined over the following 28 days. Ischaemia-reperfusion injury resulted in transient cholestasis associated with microvillar changes in biliary epithelial cell membranes and hepatocellular injury which resolved within days after reperfusion. However, in contrast to chemically-induced acute liver injuries, this was followed by sustained elevation in isoprostane E2, peri-portal inflammation and fibrosis that remained unresolved in the ischaemic reperfused lobe for at least 28 days after clamping. Administration of pregnenolone-16α-carbonitrile--a rodent-specific pregnane X receptor activator--resulted in significant reductions in cholestasis, hepatic injury, ischaemic lobe isoprostane E2 levels, peri-portal inflammation and fibrosis. Hepatic ischaemia-reperfusion injury therefore results in inflammatory and fibrotic changes that persist well beyond the initial ischaemic insult. Drug-mediated activation of the pregnane X receptor reduced these adverse changes in rats, suggesting that the pregnane X receptor is a viable drug target to reduce ischaemic-type biliary lesions in recipients of liver transplants donated after cardiac death.