P. Kaye

Narrow-band imaging with magnification in Barrett's esophagus: validation of a simplified grading system of mucosal morphology patterns against histology.

BACKGROUND AND STUDY AIMS Validation of a simplified classification of mucosal morphology in prediction of histology in Barretts esophagus using narrow-band imaging with magnification (NBI-Z) and assessing its reproducibility by endoscopists experienced in the use of NBI (NBI-experts) and by endoscopists who were new to NBI (non-NBI-experts). PATIENTS AND METHODS In a prospective cohort study of 109 patients with Barretts esophagus at a single tertiary referral center, mucosal patterns visualized in Barretts esophagus on NBI-Z were classified into four easily distinguishable types: A, round pits with regular microvasculature; B, villous/ridge pits with regular microvasculature; C, absent pits with regular microvasculature; D, distorted pits with irregular microvasculature. The NBI-Z grading was compared with the final histopathological diagnosis, and positive (PPV) and negative predictive values (NPV) were calculated. The reproducibility of the grading was then assessed by NBI-expert and non-NBI-expert endoscopists, and interobserver and intraobserver agreement were calculated using kappa statistics. RESULTS Per-biopsy analysis: In 903 out of 1021 distinct areas (87.9%) the NBI-Z grading corresponded to the histological diagnosis. Per-patient analysis: The PPV and NPV for type A pattern (columnar mucosa without intestinal metaplasia) were 100% and 97% respectively; for types B and C (intestinal metaplasia) they were 88% and 91% respectively, and for type D (high-grade dysplasia) 81% and 99% respectively. Inter- and intraobserver agreement: The mean kappa values in assessing the various patterns were 0.71 and 0.87 in the non-expert group; 0.78 and 0.91 in the expert group. CONCLUSIONS This study has validated a simplified classification of the various morphologic patterns visualized in Barretts esophagus and confirmed its reproducibility when used by NBI-expert and non-NBI-expert endoscopists.

Novel endoscopic observation in Barrett’s oesophagus using high resolution magnification endoscopy and narrow band imaging

Background High resolution magnification endoscopy with narrow band imaging (NBI) may improve the detection of specialised intestinal metaplasia (SIM) and dysplasia in Barrett’s oesophagus.

Efficacy, Safety, and Predictive Factors for a Positive Yield of EUS-Guided Trucut Biopsy: A Large Tertiary Referral Center Experience

OBJECTIVES:Endoscopic ultrasound-guided trucut biopsy (EUS–TCB) technique has the advantage of obtaining tissue for histological examination rather than for cytology alone. However, the diagnostic yield may depend on factors related to both technical aspects and the lesions sampled. Safety of EUS–TCB is yet to be established in a large number of procedures. The aim of the study was to determine factors predicting a positive diagnostic yield, and safety for EUS–TCB in a large tertiary referral center–based service.METHODS:All patients were referred for EUS-guided tissue sampling as a part of their diagnostic workup. Linear-array echoendoscope (GF-2000-OL5, KeyMed) with a 19-gauge trucut needle (Quick-Core, Wilson-Cook) was used by two operators to obtain tissue samples. Clinical data, details of the EUS–TCB, post-procedure complications, and histology were prospectively collected between May 2002 and February 2008.RESULTS:In total, 247 patients (143 men) aged 57–73 (median 66) had EUS–TCB performed. Lesions sampled were in the pancreas (113), esophagogastric wall (34), and extra-pancreatic areas (100) (lymph nodes: 52). The maximum diameter of the lesion/wall thickness ranged from 0.6 to 5.4 cm (median 3). One to five passes were made (median 3) to obtain tissue cores 2–18 mm (median 10) in length. The procedure failed in 6% of cases. The overall diagnostic accuracy was 75%. The overall complication rate was 2% (bronchopneumonia, minor hemoptysis, minor hematemesis, mucosal tear, retropharyngeal abscess) with no procedure-related deaths. Site of lesion (pancreatic vs. extra-pancreatic, P<0.032), site of biopsy (stomach vs. duodenum vs. esophagus, P<0.001), and number of passes (≤2 vs.>2, P<0.013) were predictors of a positive diagnostic yield in univariate analysis. However, only the site of biopsy (P<0.001, 95% CI: 0.58–2.32) and number of passes (P=0.05) were independent predictors in multinominal logistic regression.CONCLUSIONS:Diagnostic yield of EUS–TCB is higher when lesion is approached through the stomach and better when more than two passes were made. In this large series, the complication rate of 2% associated with EUS–TCB was similar to that reported with EUS–fine needle aspiration technique.

Acetic acid-enhanced magnification endoscopy in the diagnosis of specialized intestinal metaplasia, dysplasia and early cancer in Barrett's oesophagus.

Barretts surveillance is prone to sampling error.

Biomarkers of response to therapy in oesophago-gastric cancer

Cancer of the oesophagus, gastro-oesophageal junction (GOJ) and stomach remains a major health problem worldwide. The evidence base for the optimal management of patients with operable oesophago-gastric cancer is evolving. Accepted approaches include preoperative chemotherapy followed by surgery (oesophageal cancer), chemo-radiotherapy alone (oesophageal cancer) and perioperative chemotherapy (gastric and gastro-oesophageal adenocarcinomas). The underlying principles behind neoadjuvant therapy are to improve resectability of the tumour by tumour shrinkage/downstaging and to treat occult metastatic disease as early as possible. The response rate to cytotoxic therapy is about 40% in oesophago-gastric cancer. Available evidence suggests that a favourable histopathological response to cytotoxic therapy may be a useful positive predictive marker in oesophago-gastric cancer. However, the ability to predict tumour response in routine clinical practice is difficult and is an area of intense investigation. There is evolving evidence for the role of predictive biomarkers in cancer in general and oesophago-gastric cancer in particular. We provide an overview on the current status of radiological and biological predictive biomarkers. We have focussed on clinical translational investigations and, where appropriate, provided pre-clinical insights. Whether predictive markers will be routinely incorporated in clinical practice remains to be seen as biomarker research is expensive and the data generated from these investigations are complex. It is clear that a concerted international effort between academia and industry is critical if personalised medicine as a practical reality for our cancer patients is to be realised.

Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastro-oesophageal cancer treated with neoadjuvant chemotherapy

Aims:Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. Previously, we validated the utility of the tumour regression grade (TRG) as a histopathological marker of tumour downstaging in patients receiving platinum-based neoadjuvant chemotherapy. In this study we profiled key DNA repair and damage signalling factors and correlated them with clinicopathological outcomes, including TRG response.Methods and results:Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays (TMAs). The first set consisted of 142 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 103 gastric/gastro-oesophageal cancer cases exposed to preoperative platinum-based chemotherapy. Expressions of ERCC1, XPF, FANCD2, APE1 and p53 were investigated using immunohistochemistry.In patients who received neoadjuvant chemotherapy, favourable TRG response (TRG 1, 2 or 3) was associated with improvement in disease-specific survival (P=0.038). ERCC1 nuclear expression correlated with lack of histopathological response (TRG 4 or 5) to neoadjuvant chemotherapy (P=0.006) and was associated with poor disease-specific (P=0.020) and overall survival (P=0.040).Conclusions:We provide evidence that tumour regression and ERCC1 nuclear protein expression evaluated by immunohistochemistry are promising predictive markers in gastro-oesophageal cancer patients receiving neoadjuvant platinum-based chemotherapy.

A Role for the Vacuolating Cytotoxin, VacA, in Colonization and Helicobacter pylori–Induced Metaplasia in the Stomach

Carriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA is strongly associated with gastric adenocarcinoma. To our knowledge, we are the first to determine effects of different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach. Bacteria producing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA or producing more active forms of it, providing the first evidence of a positive role for the minimally active s2/i2 toxin. Strains producing more active toxin forms induced more severe and extensive metaplasia and inflammation in the mouse stomach than strains producing weakly active (s2/i2) toxin. We also examined the association in humans, controlling for cagPAI status. In human gastric biopsy specimens, the vacA i1 allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence of intestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA+ background.

Iron-induced mucosal pathology of the upper gastrointestinal tract: a common finding in patients on oral iron therapy.

Aims:  Upper gastrointestinal injury from iron tablets at therapeutic dose is not widely recognized. The aim was to document cases of iron‐related upper gastrointestinal (GI) pathology and to determine frequency of occurrence.

EUS-Guided Pancreatic Cyst Brushing: A Comparative Study in a Tertiary Referral Centre

CONTEXT Fluid analysis obtained by EUS guided FNA is used to aid in diagnosis and management of cystic lesions in the pancreas. Complementing fluid aspiration with brushing of cyst wall may increase the cellular yield. OBJECTIVE To compare cellular yield of pancreatic cyst FNA with and without wall brushing. DESIGN Comparative study. SETTING Tertiary referral centre. PATIENTS Fifty-one patients with cystic pancreatic lesions referred for EUS-guided aspiration/sampling were included (median age 69 years; interquartile range: 49-77 years). MAIN OUTCOME MEASURES Comparing adequacy of cellular yield between EUS-guided aspiration alone vs. EUS-guided aspiration and cyst wall brushing. INTERVENTION EUS-guided FNA and/or wall brushing (aspiration only: No. 27; brushing: No. 24). RESULTS There was no significant difference in age (P=0.496) cyst size (P=0.084) or cyst location (P=0.227) between groups. Overall 29.5%; (15/51) of samples were acellular/insufficient with no significant difference between the two groups (22.2% in the aspiration only group vs. 37.5% in the brushing group; P=0.356). The remaining samples were adequate for cytological evaluation (77.8% vs. 62.5%; aspiration only vs. brushing groups). Seventeen cases were neoplastic (8 benign, 9 malignant). The diagnostic accuracy was 61.9% and 55.0% in aspiration only and brushing groups, respectively. Two out of 4 (50.0%) patents were diagnosed as having cancer in the brushings group compared to 1/5 (20.0%) in the FNA only group (P=0.524). LIMITATIONS Non-randomised series. CONCLUSIONS The cellular yield was similar in FNA and brushing group. Greater proportion of patients with malignant cystic pancreatic lesions diagnosed by EUS sampling was in the brushing group, but this did not reach statistical significance.

Risk stratification of Barrett's oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study

BACKGROUND Barretts oesophagus predisposes to adenocarcinoma. However, most patients with Barretts oesophagus will not progress and endoscopic surveillance is invasive, expensive, and fraught by issues of sampling bias and the subjective assessment of dysplasia. We investigated whether a non-endoscopic device, the Cytosponge, could be coupled with clinical and molecular biomarkers to identify a group of patients with low risk of progression suitable for non-endoscopic follow-up. METHODS In this multicentre cohort study (BEST2), patients with Barretts oesophagus underwent the Cytosponge test before their surveillance endoscopy. We collected clinical and demographic data and tested Cytosponge samples for a molecular biomarker panel including three protein biomarkers (P53, c-Myc, and Aurora kinase A), two methylation markers (MYOD1 and RUNX3), glandular atypia, and TP53 mutation status. We used a multivariable logistic regression model to compute the conditional probability of dysplasia status. We selected a simple model with high classification accuracy and applied it to an independent validation cohort. The BEST2 study is registered with ISRCTN, number 12730505. FINDINGS The discovery cohort consisted of 468 patients with Barretts oesophagus and intestinal metaplasia. Of these, 376 had no dysplasia and 22 had high-grade dysplasia or intramucosal adenocarcinoma. In the discovery cohort, a model with high classification accuracy consisted of glandular atypia, P53 abnormality, and Aurora kinase A positivity, and the interaction of age, waist-to-hip ratio, and length of the Barretts oesophagus segment. 162 (35%) of 468 of patients fell into the low-risk category and the probability of being a true non-dysplastic patient was 100% (99% CI 96-100) and the probability of having high-grade dysplasia or intramucosal adenocarcinoma was 0% (0-4). 238 (51%) of participants were classified as of moderate risk; the probability of having high-grade dysplasia was 14% (9-21). 58 (12%) of participants were classified as high-risk; the probability of having non-dysplastic endoscopic biopsies was 13% (5-27), whereas the probability of having high-grade dysplasia or intramucosal adenocarcinoma was 87% (73-95). In the validation cohort (65 patients), 51 were non-dysplastic and 14 had high-grade dysplasia. In this cohort, 25 (38%) of 65 patients were classified as being low-risk, and the probability of being non-dysplastic was 96·0% (99% CI 73·80-99·99). The moderate-risk group comprised 27 non-dysplastic and eight high-grade dysplasia cases, whereas the high-risk group (8% of the cohort) had no non-dysplastic cases and five patients with high-grade dysplasia. INTERPRETATION A combination of biomarker assays from a single Cytosponge sample can be used to determine a group of patients at low risk of progression, for whom endoscopy could be avoided. This strategy could help to avoid overdiagnosis and overtreatment in patients with Barretts oesophagus. FUNDING Cancer Research UK.