James Catton

Barrett's dysplasia and the Vienna classification: reproducibility, prediction of progression and impact of consensus reporting and p53 immunohistochemistry.

Aims:  The Vienna classification is used to classify dysplasia in Barrett’s oesophagus (BO), but reproducibility and value of diagnosis of lower grades in particular are often questioned. The aim was to test the diagnostic variability and correlation with patient outcome and to attempt to define histological features causing discrepant diagnoses, as well as to test the impact of adding p53 immunohistochemistry on reproducibility and prediction of outcome.

Sarcopenia is associated with toxicity in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer

BACKGROUND Patients with potentially curative oesophago-gastric cancer typically undergo neo-adjuvant chemotherapy prior to surgery. The majority of anti-cancer drugs have a narrow therapeutic index. The aim of this study was to determine if features of body composition, assessed using computed tomography (CT) scans, may be predictive of dose-limiting toxicity (DLT) in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer. The influence of sarcopenia and DLT on overall survival was also evaluated. METHODS 89 Patients having potentially curative oesophago-gastric cancer surgery were studied. Patients studied had histologically confirmed oesophago-gastric cancer with no evidence of distant metastasis on pre-operative staging. CT scan was performed in all cases at diagnosis. DLT was defined as toxicity leading to postponement of treatment, a drug dose reduction or definitive interruption of drug administration. RESULTS DLT occurred in 37 out of 89 patients (41.6%) undergoing chemotherapy. Sarcopenia (odds ratio, 2.95; 95% confidence interval, 1.23-7.09; p = 0.015) was associated with DLT on multivariate analysis. Median overall survival for patients who were sarcopenic was 569 days (IQ range: 357-1230 days) vs. 1013 days (IQ range: 496-1318 days) for patients who were not sarcopenic (p = 0.04). There was no significant difference in overall survival in patients who experienced DLT compared with those that did not (p = 0.665). CONCLUSIONS Sarcopenia is a significant predictor of DLT in oesophago-gastric cancer patients undergoing neo-adjuvant chemotherapy. These results raise the potential for use of assessment of skeletal muscle mass using CT scans to predict toxicity and individualize chemotherapy dosing.

Novel staining pattern of p53 in Barrett’s dysplasia – the absent pattern

Sir: Barrett’s oesophagus (BO) is conversion of oesophageal squamous mucosa to a glandular phenotype, and is a consequence of gastro-oesophageal reflux. This is a precursor to oesophageal adenocarcinoma (OA), which is rising rapidly in western countries and carries a poor prognosis. This pathway is characterized by intestinal metaplasia and increasing grades of dysplasia before cancer supervenes. Recognizing dysplasia early allows close monitoring as well as treatment preventing OA or cure at an early stage. The recog‘nition of dysplasia by pathologists is critical, and while pathologists can recognize dysplasia reproducibly this may sometimes be difficult. Therefore additional prognostic markers would be helpful. Several studies have shown that p53 overexpression is associated closely with dysplasia and predicts progression in its own right. Overexpression is a consequence of mutations which stabilize the inactivated protein. However, a subset of unequivocal Barrett’s dysplasia cases are negative for p53. In some cases p53 may not be involved in the dysplastic progression, but in other cases truncating TP53 mutations or epigenetic silencing may cause protein inactivation. In these cases it is lack of expression rather than overexpression which would be expected. With this in mind, we re-analysed the dysplastic and indefinite p53negative cases from our previously published study to see if this pattern might have accounted for some p53negative dysplasias and to assess its significance prognostically. As described in detail previously, cases of oesophageal glandular dysplasia were identified from pathology databases at Queens Medical Centre and City Hospital, Nottingham between 1987 and 2004. Thirtytwo random cases of BO without dysplasia were also included. Five pathologists blinded to the original diagnosis classified each case independently using the revised Vienna classification. One pathologist scored each p53-stained section (D07 antibody with microwave antigen retrieval; Dako, Ely, UK) as positive, negative or not representative. A consensus Vienna score for each case was determined. Cases negative for p53 but with a study diagnosis of dysplasia or indefinite for dysplasia were reviewed again by two pathologists (PVK and MI). Two distinct patterns were identified: (i) wild-type (p53-wt) with weak immunoreactivity in dysplastic ⁄ atypical epithelium similar to the background non-dysplastic epithelium and (ii) absent staining (p53-abs) with complete lack of staining in dysplastic ⁄ atypical epithelium relative to weak positivity in surrounding non-dysplastic epithelium (Figure 1). This contrasted with positive staining described above, where the dysplastic epithelium showed much stronger staining than the surrounding non-dysplastic epithelium (p53-pos). Patient records were examined to determine length of followup and progression. A total of 175 cases were identified. In 33 cases p53 staining could not be assessed due to lack of representative tissue, 43 cases were p53-positive (42 dysplasia, one indefinite) and 99 p53-negative (11 dysplasia, 10 indefinite). Re-analysis of categories 2–4 p53-negatives are shown in Table 1. The 10 indefinite for dysplasia cases all had staining in equivocal areas indistinguishable from background non-dysplastic Barrett’s epithelium (p53-wt). Of the 11 cases with dysplasia, five showed the absent pattern of staining in dysplastic areas (p53-abs), while six showed weak staining indistinguishable from background Barrett’s epithelium (p53-wt) (Table 1). Of the 40 patients with positive p53 with follow-up data available, 28 progressed within 10 years. Of the 10 patients with indefinite for dysplasia and p53-wt, two progressed within 10 years. Of the 11 dysplastic cases, all five with p53-abs progressed clinically or histologically but only two of six with p53-wt progressed; four remained alive with regression without intervention. We and others have shown that in addition to dysplasia, immunohistochemical analysis of p53 overexpression is a powerful predictor of progression in BO. Herein we have identified a novel pattern of complete absence of staining (p53-abs) which has a similar predictive value to the classical pattern of overexpression (p53-pos). This should add power to the technique of p53 immunohistochemistry by including cases with abnormal expression of the protein which was formally regarded as negative. p53-abs may correlate with truncating mutations in TP53 which cannot be recognized by the commonly used D07 antibody. Alternatively, a variety of other non-mutational mechanisms for TP53 inactivation have been described. The proportion of oesophageal cancers harbouring mutant p53 ranges up to 80%. Of our assessable definite dysplasia cases, 47 of 53 (89%) showed an abnormal p53 immunophenotype.

The routine microbiological screening of central venous catheters in home parenteral nutrition patients

BACKGROUND & AIMS Catheter-related bloodstream infection (CRBSI) is a major complication for patients receiving home parenteral nutrition (HTPN). Endoluminal sampling techniques allow the diagnosis of CRBSI without catheter removal and may allow the screening of asymptomatic patients. METHODS Over a 5-year period, patients receiving HTPN were offered screening on a 3 monthly basis. All patients had tunnelled cuffed Hickman lines. All were asymptomatic at the time of screening, which took the form of either endoluminal brushing or quantitative cultures on through-line blood. RESULTS Thirty-two patients were suitable for inclusion within the study period (10 male, median age 51 (iqr 46-61)) years with 30 of these having a least one screening performed. Four had positive screening results and underwent appropriate treatment. Of the remainder, 12 presented with at least one clinical episode of CRBSI and 14 had neither clinical CRBSI nor a positive screening result. The combined clinical and screening CRBSI rate was 0.39 episodes per catheter year. CONCLUSION Although routine microbiological catheter screening can detect subclinical infections in HTPN patients the positive rate is low with the majority of patients still presenting clinical. Identification of higher risk patients and appropriate alterations to screening frequency may improve its value further.

Adherence to Enhanced Recovery after Surgery Protocols across a High-Volume Gastrointestinal Surgical Service

Background and Aims: Enhanced recovery after surgery (ERAS) has been shown to improve outcomes for patients following gastrointestinal surgery. Data on protocol adherence and how this impacts on outcome are limited. This study examines how protocol adherence changes over time and determines how this impacts on outcome across a large-volume gastrointestinal surgical service. Materials and Methods: A prospective review of patients eligible for colorectal, liver and oesophagogastric ERAS over two 3-month periods in 2010 and 2011 was performed. End points included: length of stay (LOS), overall protocol adherence, individual modality adherence, reason for pathway deviation and patient outcomes. Results: 172 patients (110 colorectal, 31 liver and 31 oesophagogastric) were evaluated. For each sub-speciality, the introduction of ERAS led to significant reductions in LOS that were sustained for the duration of the study. Adherence was achieved across 60% (colorectal), 75% (liver) and 88% (oesophagogastric) of individual pathway modalities. The major causes of pathway deviation were: post-operative nausea and vomiting (colorectal), pain (liver) and pulmonary complications (oesophagogastric). Conclusions: Large-scale implementation of ERAS at a high-volume centre is feasible and offers many of the benefits demonstrated in controlled trials, but adherence may diminish over time.

Initial Experience With the Use of Biological Implants for Soft Tissue and Chest Wall Reconstruction in Thoracic Surgery

BACKGROUND Synthetic materials have traditionally been used for tissue reconstruction in thoracic surgery. New biomaterials have been tested in other areas of surgery with good results. The aim of our study is to evaluate our initial experience using prostheses in extended thoracic surgery. METHODS A review was performed of all patients who underwent extended surgical procedures requiring soft tissue reconstruction with bioprosthetic materials after thoracic surgery from August 2009 to August 2011. A total of 44 consecutive patients were included. Operations involved radical pleurectomy and decortication for mesothelioma (n = 29), extended operations for thoracic malignancies (n = 8), surgery for trauma or perforated organs or complications (n = 6), and for benign infectious causes (n = 1). RESULTS A total of 76 patches were used in 44 patients (median of 2; range 1 to 3 per patient). Median hospital stay was 13 (range 5 to 149) days. Three patients died during the postoperative period (6.8%); pulmonary embolism 5 days after intrapericardial pneumonectomy with chest wall reconstruction, fatal pneumonia 26 days after radical pleurectomy and decortication for mesothelioma, and bronchopleural fistula 11 days after pneumonectomy with diaphragm and atrium excision for lung cancer after initial chemoradiotherapy. No other surgical exploration or removal of patches has been required for infection. CONCLUSIONS Our initial experience of using bioprosthetic patches for soft tissue reconstruction in thoracic surgery has proven satisfactory with overall acceptable results. The infection rates are low even when a proportion of procedures were performed under contaminated environments. Biologic prosthesis should be part of the surgical options to reconstruct soft tissues in thoracic surgery.

Achieving long term survival in oesophagectomy patients aged over 75

Aims Surgical resection is often the only curative treatment for oesophageal cancer. The aim of this retrospective cohort study was to analyse outcomes following oesophageal resection in patients aged 75 years and older and the impact of an Enhanced Recovery after Surgery (ERAS) program in this cohort. Methods Patients aged over 75 years undergoing oesophagectomy between 2003 and 2013 were identified from a single centre using an electronic database. Data on pre-operative comorbidity, tumour stage and length of hospital stay (LOS) were collected. Complications were classified according to the Clavien-Dindo system. Thirty day, 1- and 5-year mortality rates were calculated. Results 147 patients were identified with a median age of 78.5 (IQR 76.7–80.9). 33% (n = 44) had a grade 3 complication or higher. Median LOS in hospital was 16 days (IQR 13.0–22.0). Thirty-day mortality was 3.4%, 1-year and 5-year survival was 65% and 21% respectively. 45% of patients were enrolled into an Enhanced Recovery After Surgery program and they demonstrated a significantly reduced length of stay from 18 to 14 days (p = 0.005) and 30-day mortality from 6.2% to 0% (p = 0.04) compared to the time period before the program. Conclusion Long-term survival is achievable in patients aged over 75 years.

Pizza, beer, amylase, lipase and the acute abdomen

A previously healthy 16-year-old male student was admitted with acute abdominal pain after eating two large pizzas and drinking five pints (approximately 2.8 l) of beer (alcohol content 4.5%). Initial assessment revealed epigastric tenderness with elevated serum amylase (380 IU/l, normal 30–110 IU/l) and lipase (4398 IU/l, normal 23–300 IU/l) concentrations. There was no free gas on the chest radiograph. The patient developed increasing abdominal pain, tenderness, tachycardia and a lactic acidosis (pH 7.20, lactate 2.91 mmol/l) within 6 h. Contrast-enhanced abdominal CT (figure 1) was done 8 h after admission. Figure 1 Contrast-enhanced …

Impact of straight to test pathways on time to diagnosis in oesophageal and gastric cancer.

Background Cancer survival in the UK has doubled in the last 40 years; however, 1-year and 5-year survival rates are still lower than other countries. One cause may be a delay between referral into secondary care and subsequent investigation. We set out to evaluate the impact of a straight to test pathway (STTP) on time to diagnosis for upper gastrointestinal (UGI) cancer. Methods Six hospital Trusts across the East Midlands Clinical Network introduced a STTP enabling general practitioners to refer patients with suspected UGI cancer (oesophageal/gastric) for immediate investigation, without the need to see a hospital specialist first. Data were collected for all patients referred between 2013 and 2015 with suspected UGI cancer and stratified by STTP or traditional referral pathway. Overall time from referral to diagnosis was compared. Data from two Trusts who did not implement STTP acted as control. Results 340 patients followed the STTP pathway and 495 followed the traditional route. STTP saved a mean of 7 days from referral to treatment (with a 95% CI of 3 to 11 days, p<0.008) and a mean of 16 days from referral to diagnosis, when compared with a traditional referral pathway. The number of diagnostic tests performed using STTP or traditional referral pathways were similar. Conclusion A STTP is associated with an overall reduction of 1 week from referral to treatment for UGI cancer. The approach is feasible and did not require more resource. Larger studies are required to assess whether this time saving translates into improved cancer outcomes.

OC-039 The feasibility, safety, and efficacy of per-oral endoscopic myotomy for achalasia: results from a uk tertiary referral centre

Introduction Per-oral endoscopic myotomy (POEM) is a novel technique which involves performing a myotomy endoscopically after creating a submucosal tunnel. Despite being widely adopted in the USA, Europe and Asia, its introduction into the UK has been limited. We describe one of the first series of POEM procedures in the UK, assessing its feasibility, safety and efficacy. Method POEM was performed as inpatient under general anaesthesia with endotracheal intubation using the Olympus video endoscopy system. Two experienced endoscopists performed the procedures after undergoing hands on training in live animal models. The procedure involved mucosal entry, submucosal tunnelling, myotomy and clip closure of mucosal defect. The Endolumenal Functional Lumen Imaging Probe (EndoFLIP) was used to assess the gastroesophageal junction (GOJ) distensibility at balloon volumes of 30 and 40 ml at the start and end of procedures. Contrast swallow was performed 24–48 hours prior to discharge. Eckardt scores were prospectively recorded at the time initial clinic visit and at follow up visits, 4–8 weeks post procedure. Results Twenty six patients underwent POEM at our institution. Median age was 51 years (interquartile range (IQR) 42–60) and 69% were males. 17 patients (65%) had type II achalasia; 5 (19%) were type I; 2 (8%) type III; and 2 (8%) unclassified. Procedure failed in 2 patients who were excluded from the analysis. Median length of hospital stay was 3 days (IQR 2–3) days. Median (IQR) GOJ pressures reduced from 18.2 (15.3–27.9) and 33.0 (28.2–40.5) to 14.2 (12.4–18) and 23.1 (18–26.3) mmHg at 30 ml (p=0.10) and 40 ml (p=0.002) volumes, respectively. Median (IQR) Eckardt score was 8 (6-9) pre-procedure and 1 (1-2) post procedure (p<0.001). Perioperative complications included pneumoperitoneum (n=1) and mucosal laceration (n=3) all treated successfully. No post-operative complications occurred during a median (IQR) follow up of 6 months (1-10). Conclusion Evidence from this early series of POEM procedures in the UK confirms its feasibility, safety and efficacy in the treatment of achalasia by experienced endoscopists with adequate training. The use of EndoFLIP assists in assessing response to myotomy immediately post procedure. Disclosure of Interest None Declared