Nicholas D. Maynard

Enhanced recovery for esophagectomy: a systematic review and evidence-based guidelines.

Objective:This article aims to provide the first systematic review of enhanced recovery after surgery (ERAS) programs for esophagectomy and generate guidelines. Background:ERAS programs use multimodal approaches to reduce complications and accelerate recovery. Although ERAS is well established in colorectal surgery, experience after esophagectomy has been minimal. However, esophagectomy remains an extremely high-risk operation, commonly performed in patients with significant comorbidities. Consequently, ERAS may have a significant role to play in improving outcomes. No guidelines or reviews have been published in esophagectomy. Methods:We undertook a systematic review of the PubMed, EMBASE, and the Cochrane databases in July 2012. The literature was searched for descriptions of ERAS in esophagectomy. Components of successful ERAS programs were determined, and when not directly available for esophagectomy, extrapolation from related evidence was made. Graded recommendations for each component were then generated. Results:Six retrospective studies have assessed ERAS for esophagectomy, demonstrating favorable morbidity, mortality, and length of stay. Methodological quality is, however, low. Overall, there is little direct evidence for components of ERAS, with much derived from nonesophageal thoracoabdominal surgery. Conclusions:ERAS in principle seems logical and safe for esophagectomy. However, the underlying evidence is poor and lacking. Despite this, a number of recommendations for practice and research can be made.

Additional benefit of 18F-fluorodeoxyglucose integrated positron emission tomography/computed tomography in the staging of oesophageal cancer

Objective18F-fluorodeoxyglucose positron emission tomography (FDG PET) has been shown to improve the accuracy of staging in oesophageal cancer. We assessed the benefit of PET/CT over conventional staging and determined if tumour histology had any significant impact on PET/CT findings.MethodsA retrospective cohort study, reviewing the results from 200 consecutive patients considered suitable for radical treatment, undergoing routine PET/CT staging comparing the results from CT and endoscopic ultrasound, as well as multi-disciplinary team records. Adenocarcinoma and squamous cell carcinoma were compared for maximum Standardised Uptake Value (SUVmax), involvement of local lymph nodes and distant metastases.ResultsPET/CT provided additional information in 37 patients (18.5%) and directly altered management in 34 (17%): 22 (11%) were upstaged; 15 (7.5%) were downstaged, 12 of whom (6%) received radical treatment. There were 11 false negatives (5.5%) and 1 false positive (0.5%). SUVmax was significantly lower for adenocarcinoma than squamous cell carcinoma (median 9.1 versus 13.5, p = 0.003).ConclusionsStaging with PET/CT offers additional benefit over conventional imaging and should form part of routine staging for oesophageal cancer. Adenocarcinoma and squamous cell carcinoma display significantly different FDG-avidity.

Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy

How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C>A and TT>CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful.

Nonoperative Management of Appendicitis in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Received July 27, 2016; Revised September 13, 2016; Acce 13, 2016. From the Oxford OesophagoGastric Centre, Churchill Hos Kafsi, Gillies, Maynard) and the Department of Emergenc Radcliffe Hospital (Hammer, Gilmour), Oxford University Foundation Trust; and NIHR Oxford Biomedical Resear dlay), Churchill Hospital, Oxford, UK. Correspondence address: John M Findlay, BMedSci, MRCS; Oxford OesophagoGastric Centre, Churchill H OX3 7LJ, UK. email: john.findlay@oncology.ox.ac.uk

The effect of formalizing enhanced recovery after esophagectomy with a protocol.

Enhanced recovery after surgery (ERAS) pathways aim to accelerate functional return and discharge from hospital. They have proven effective in many forms of surgery, most notably colorectal. However, experience in esophagectomy has been limited. A recent study reported significant reductions in pulmonary complications, mortality, and length of stay following the introduction of an ERAS protocol alone, without the introduction of any clinical changes. We instituted a similar change 16 months ago, introducing a protocol to provide a formal framework, for our existing postoperative care. This retrospective analysis compared outcome following esophagectomy for the 16 months before and 20 months after this change. Data were collected from prospectively maintained secure web-based multidisciplinary databases. Complication severity was classified using the Clavien-Dindo scale. Operative mortality was defined as death within 30 days of surgery, or at any point during the same hospital admission. Lower respiratory tract infection was defined as clinical evidence of infection, with or without radiological signs. Respiratory complications included lower respiratory tract infection, pleural effusion (irrespective of drainage), pulmonary collapse, and pneumothorax. Statistical analysis was performed using SPSS v21. One hundred thirty-two patients underwent esophagectomy (55 protocol group; 77 before). All were performed open. There were no differences between the two groups in terms of age, gender, operation, use of neoadjuvant therapy, cell type, stage, tumor site, or American Society of Anesthesiologists grade. Median length of stay was 14.0 days (protocol) compared with 12.0 before (interquartile range 9-19 and 9.5-15.5, respectively; P = 0.073, Mann-Whitney U-test). Readmission within 30 days of discharge occurred in five (9.26%) and six (8.19%; P = 1.000, Fishers exact test). There were four in-hospital deaths (3.03%): one (1.82%) and three (3.90%), respectively (P = 0.641). There were no differences in the severity of complications (P = non-significant; Pearsons chi-squared). There were no differences in the type of complications occurring in either group. The protocol was completed successfully by 26 (47.3%). No baseline factors were predictive of this. In contrast to previous studies, we did not demonstrate any improvement in outcome by formalizing our existing pathway using a written protocol. Consequently, improvements in short-term outcome from esophagectomy within ERAS would seem to be primarily due to improvements in components of perioperative care. Consequently, we would recommend that centers introducing new (or reviewing existing) ERAS pathways for esophagectomy focus on optimizing clinical aspects of such standardized pathways.

EpCAM and gpA33 are markers of Barrett's metaplasia.

Aims: To characterise a specific and sensitive marker of Barrett’s metaplasia (BM). Methods: Cases of normal oesophageal squamous mucosa (11 fresh endoscopic biopsies and 10 formalin fixed, paraffin embedded tissue blocks), BM (11 biopsies and 11 tissue blocks), and normal gastric body mucosa (five biopsies and five tissue blocks) were analysed using reverse transcriptase PCR, Western blotting, and immunohistochemistry for EpCAM, and reverse transcriptase PCR for gpA33. Results: Strong EpCAM mRNA expression was detected in all the BM cases, in contrast to weak expression in all the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Strong gpA33 mRNA expression was detected in all the BM cases, in contrast to weak expression in a quarter of the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Western blotting showed EpCAM protein expression in all the BM cases and in none of the normal gastric or oesophageal mucosal samples tested. Immunohistochemistry showed strong EpCAM protein expression in BM and complete absence of expression in normal oesophageal squamous epithelium. Scattered EpCAM expressing cells were found in the gland bases of normal gastric body mucosa. Conclusions: EpCAM protein and gpA33 mRNA expressions are specific and sensitive markers of BM.

Left thoracoabdominal esophagectomy: results from a single specialist center.

The left thoracoabdominal approach to esophagectomy is not widely performed, despite offering excellent exposure to tumors of the esophagogastric junction. Criticisms of the approach have focused on historically high rates of mortality, complications, and positive resection margins. Our aim was to determine whether left thoracoabdominal esophagectomy could combine a radical oncological resection with acceptably low mortality and morbidity. A retrospective cohort study of all left thoracoabdominal esophagectomies was performed at a single specialist center over an 11-year period. Primary outcomes were in-hospital mortality, complications, resection margin involvement, and lymph node yield; secondary outcomes were 1-year and 5-year survival. Two hundred eleven esophagectomies were performed. In-hospital mortality was 5.7% (12/211). One hundred one subjects (47.9%) had an uncomplicated recovery; 110 subjects (52.1%) developed at least one complication. There were 15 clinically significant anastomotic leaks (7.1%). Twenty-four subjects (11.4%) required emergency reoperation, the most common indication being anastomotic leakage. Complete tumor excision (R0 resection) was achieved in 151 of 211 cases (71.6%); median lymph node yield was 24. One-year and 5-year survival rates were 70% (147/211) and 21% (24/116), respectively. Left thoracoabdominal esophagectomy can combine a radical oncological resection with acceptably low mortality and morbidity.

Attempted validation of the NUn score and inflammatory markers as predictors of esophageal anastomotic leak and major complications

The ability to predict complications following esophagectomy/extended total gastrectomy would be of great clinical value. A recent study demonstrated significant correlations between anastomotic leak (AL) and numerical values of C-reactive protein (CRP), white cell count (WCC) and albumin measured on postoperative day (POD) 4. A predictive model comprising all three (NUn score >10) was found to be highly sensitive and discriminant in predicting AL and complications. We attempted a retrospective validation in our center. Data were collected on all resections performed during a 5-year period (April 2008-2013) using prospectively maintained databases. Our biochemistry laboratory uses a maximum CRP value (156 mg/L), unlike that of the original study; otherwise all variables and outcome measures were comparable. Analysis was performed for all patients with complete blood results on POD4. Three hundred twenty-six patients underwent resection, of which 248 had POD4 bloods. There were 21 AL overall (6.44%); 16 among those with complete POD4 blood results (6.45%). There were 8 (2.45%) in-hospital deaths; 7 (2.82%) in those with POD4 results. No parameters were associated with AL or complication severity on univariate analysis. WCC was associated with AL in multivariate binary logistic regression with albumin and CRP (OR 1.23 [95% CI 1.03-1.47]; P = 0.021). When a binary variable of CRP ≥ 156 mg/L was used rather than an absolute value, no factors were significant. Mean NUn was 8.30 for AL, compared with 8.40 for non-AL (P = 0.710 independent t-test). NUn > 10 predicted 0 of 16 leaks (sensitivity 0.00%, specificity 94.4%, receiver operator curve [ROC] area under the curve [AUC] 0.485; P = 0.843). NUn > 7.65 was 93% sensitive and 21.6% specific. ROC for WCC alone was comparable with NUn (AUC 0.641 [0.504-0.779]; P = 0.059; WCC > 6.89 93.8% sensitive, 20.7% specific; WCC > 15 6.3% sensitive and 97% specific). There were no associations between any parameters and other complications. In a comparable cohort with the original study, we demonstrated a similar multivariate association between WCC alone on POD4 and subsequent demonstration of AL, but not albumin or CRP (measured up to 156 mg/L). The NUn score overall (calculated with this caveat) and a threshold of 10 was not found to have clinical utility in predicting AL or complications.

The Management of a Patient with an Operable Carcinoma of the Oesophagus

Patients with operable oesophageal cancer should receive a balanced discussion of the complex issues outlined above, from both the surgical and oncological teams. Patients often develop an unshakeable confidence in the treatment described during their first clinical consultation and specialist upper gastrointestinal nurses are key to maintaining equipoise in the giving of clinical information. Individual patient preferences, based on personality and previous experience, are paramount in making treatment choices. Where possible, patients should be entered into clinical trials such as the CRUK SCOPE 1 trial of definitive chemoradiotherapy with or without cetuximab and the MRC OE05 trial of chemotherapy before surgery in adenocarcinoma of the oesophagus; the availability of such trials may influence treatment recommendations. A feasibility study is due to open soon to establish whether a full multicentre randomised controlled trial comparing definitive CRT with treatment including surgery is possible in the UK. The study will establish methods for best communicating the treatment options to patients eligible for either treatment approach (Blazeby, personal communication). Outside of clinical trials, we would currently recommend the following approach: For a patient with an operable squamous cell carcinoma, we would recommend primary CRT, offering primary organ preservation in parallel with squamous cancers of other sites including the head and neck, anus and cervix, with surgery for selected patients who have residual or relapsed disease. For a similar patient with an adenocarcinoma, we would recommend pre-operative chemotherapy followed by an oesophagectomy … but then again we are biased!

Individual risk modelling for esophagectomy: a systematic review.

IntroductionA number of models have been applied to predict outcomes from esophagectomy. This systematic review aimed to compare their clinical credibility, methodological quality and performance.MethodsA systematic review of the PubMed, EMBASE and Cochrane databases was performed in October 2012. Model and study quality were appraised using the framework of Minne et al.ResultsTwenty studies were included in total; these were heterogeneous, retrospective and conducted over a number of years; all models were generated via logistic regression. Overall mortality was high, and consequently not representative of current practice. Clinical credibility and methodological quality were variable, with frequent failure to perform internal validation and variable presentation of calibration and discrimination metrics. P-POSSUM demonstrated the best calibration and discrimination for predicting mortality. Other than the Southampton score (which has yet to be externally validated) and the Amsterdam score, no studies had utility in predicting complications.ConclusionWhilst a number of models have been developed, adapted or trialled, due to numerous limitations, larger and more contemporary studies are required to develop and validate models further. The role of alternative techniques such as decision tree analysis and artificial neural networks is not known.