Almond LM, Hutchings J, Kendall C, et al.
Assessment of a custom-built Raman spectroscopic probe for diagnosis of early oesophageal neoplasia.
J Biomed Opt. 2012; 17(8):081421-1 [PubMed]

We evaluate the potential of a custom-built fiber-optic Raman probe, suitable for in vivo use, to differentiate between benign, metaplastic (Barrett's oesophagus), and neoplastic (dysplastic and malignant) oesophageal tissue ex vivo on short timescales. We measured 337 Raman spectra (λ(ex)=830 nm; P(ex)=60 mW; t=1 s) using a confocal probe from fresh (298) and snap-frozen (39) oesophageal tissue collected during surgery or endoscopy from 28 patients. Spectra were correlated with histopathology and used to construct a multivariate classification model which was tested using leave one tissue site out cross-validation in order to evaluate the diagnostic accuracy of the probe system. The Raman probe system was able to differentiate, when tested with leave one site out cross-validation, between normal squamous oesophagus, Barrett's oesophagus and neoplasia with sensitivities of (838% to 6%) and specificities of (89% to 99%). Analysis of a two group model to differentiate Barrett's oesophagus and neoplasia demonstrated a sensitivity of 88% and a specificity of 87% for classification of neoplastic disease. This fiber-optic Raman system can provide rapid, objective, and accurate diagnosis of oesophageal pathology ex vivo. The confocal design of this probe enables superficial mucosal abnormalities (metaplasia and dysplasia) to be classified in clinically applicable timescales paving the way for an in vivo trial.

Gloucestershire Hospitals NHS Trust, Biophotonics Research Unit, Gloucester, Gloucestershire GL1 3NN

Wright E, Schofield PT, Seed P, Molokhia M
Bisphosphonates and risk of upper gastrointestinal cancer--a case control study using the General Practice Research Database (GPRD).
PLoS One. 2012; 7(10):e47616 [PubMed] Free Access to Full Article

BACKGROUND: Concerns have been raised as to the safety of bisphosphonates; in particular a possible link between bisphosphonate use and upper gastrointestinal (GI) cancer. Two published studies using different study populations but drawn from earlier versions of the same national UK database, reached differing conclusions: one finding no evidence for an increase in the risk of gastric or oesophageal cancer in bisphosphonate users and one finding a small but significantly increased risk of oesophageal cancer linked to duration of bisphosphonate use.
METHODOLOGY/ PRINCIPAL FINDINGS: Design-A case control study comparing bisphosphonate prescribing in cases of upper GI cancer from 1995 to 2007 using UK primary care electronic health records (GPRD). Main Outcome Measure-Relative Risk (approximated to Odds Ratio for rare events) for oesophageal and gastric cancer development in bisphosphonate users compared to non-users. The odds of being a case of oesophageal cancer, adjusted for smoking status, were significantly increased in women who had had one or more bisphosphonate prescriptions, odds ratio 1.54 (95% CI 1.27-1.88) compared to non-users. There was no significant effect on gastric cancer in women, odds ratio adjusted for smoking status, 1.06 (95% CI 0.83-1.37) and also no apparent risk in men for either oesophageal or gastric cancer, odds ratio adjusted for smoking status 0.78 (95%CI 0.56-1.09) and 0.87 (95% CI 0.55-1.36) respectively. CONCLUSIONS/ SIGNIFICANCE: Our results support a small but significant increased risk of oesophageal cancer in women prescribed bisphosphonates and is based on the largest number of exposed cases to date in the UK.

Department of Primary Care and Public Health Sciences, King's College London, London

Benaglia T, Sharples LD, Fitzgerald RC, Lyratzopoulos G
Health benefits and cost effectiveness of endoscopic and nonendoscopic cytosponge screening for Barrett's esophagus.
Gastroenterology. 2013; 144(1):62-73.e6 [PubMed]

BACKGROUND & AIMS: We developed a model to compare the health benefits and cost effectiveness of screening for Barrett's esophagus by either Cytosponge™ or by conventional endoscopy vs no screening, and to estimate their abilities to reduce mortality from esophageal adenocarcinoma.
METHODS: We used microsimulation modeling of a hypothetical cohort of 50-year-old men in the United Kingdom with histories of gastroesophageal reflux disease symptoms, assuming the prevalence of Barrett's esophagus to be 8%. Participants were invited to undergo screening by endoscopy or Cytosponge (invitation acceptance rates of 23% and 45%, respectively), and outcomes were compared with those from men who underwent no screening. We estimated the number of incident esophageal adenocarcinoma cases prevented and the incremental cost-effectiveness ratio of quality-adjusted life years (QALYs) of the different strategies. Patients found to have high-grade dysplasia or intramucosal cancer received endotherapy. Model inputs included data on disease progression, test accuracy, post-treatment status, and surveillance protocols. Costs and benefits were discounted at 3.5% per year. Supplementary and sensitivity analyses comprised esophagectomy management of high-grade dysplasia or intramucosal cancer, screening by ultrathin nasal endoscopy, and different assumptions of uptake of screening invitations for either strategy.
RESULTS: We estimated that compared with no screening, Cytosponge screening followed by treatment of patients with dysplasia or intramucosal cancer costs an additional $240 (95% credible interval, $196-$320) per screening participant and results in a mean gain of 0.015 (95% credible interval, -0.001 to 0.029) QALYs and an incremental cost-effectiveness ratio of $15.7 thousand (K) per QALY. The respective values for endoscopy were $299 ($261-$367), 0.013 (0.003-0.023) QALYs, and $22.2K. Screening by the Cytosponge followed by treatment of patients with dysplasia or intramucosal cancer would reduce the number of cases of incident symptomatic esophageal adenocarcinoma by 19%, compared with 17% for screening by endoscopy, although this greater benefit for Cytosponge depends on more patients accepting screening by Cytosponge compared with screening by endoscopy.
CONCLUSIONS: In a microsimulation model, screening 50-year-old men with symptoms of gastroesophageal reflux disease by Cytosponge is cost effective and would reduce mortality from esophageal adenocarcinoma compared with no screening.

Medical Research Council, Biostatistics Unit, Cambridge

Murray IA, Palmer J, Waters C, Dalton HR
Predictive value of symptoms and demographics in diagnosing malignancy or peptic stricture.
World J Gastroenterol. 2012; 18(32):4357-62 [PubMed] Free Access to Full Article

AIM: To determine which features of history and demographics predict a diagnosis of malignancy or peptic stricture in patients presenting with dysphagia.
METHODS: A prospective case-control study of 2000 consecutive referrals (1031 female, age range: 17-103 years) to a rapid access service for dysphagia, based in a teaching hospital within the United Kingdom, over 7 years. The service consists of a nurse-led telephone triage followed by investigation (barium swallow or gastroscopy), if appropriate, within 2 wk. Logistic regression analysis of demographic and clinical variables was performed. This includes age, sex, duration of dysphagia, whether to liquids or solids, and whether there are associated features (reflux, odynophagia, weight loss, regurgitation). We determined odds ratio (OR) for these variables for the diagnoses of malignancy and peptic stricture. We determined the value of the Edinburgh Dysphagia Score (EDS) in predicting cancer in our cohort. Multivariate logistic regression was performed and P < 0.05 considered significant. The local ethics committee confirmed ethics approval was not required (audit).
RESULTS: The commonest diagnosis is gastro-esophageal reflux disease (41.3%). Malignancy (11.0%) and peptic stricture (10.0%) were also relatively common. Malignancies were diagnosed by histology (97%) or on radiological criteria, either sequential barium swallows showing progression of disease or unequivocal evidence of malignancy on computed tomography. The majority of malignancies were esophago-gastric in origin but ear, nose and throat tumors, pancreatic cancer and extrinsic compression from lung or mediastinal metastatic cancer were also found. Malignancy was statistically more frequent in older patients (aged >73 years, OR 1.1-3.3, age < 60 years 6.5%, 60-73 years 11.2%, > 73 years 11.8%, P < 0.05), males (OR 2.2-4.8, males 14.5%, females 5.6%, P < 0.0005), short duration of dysphagia (≤ 8 wk, OR 4.5-20.7, 16.6%, 8-26 wk 14.5%, > 26 wk 2.5%, P < 0.0005), progressive symptoms (OR 1.3-2.6: progressive 14.8%, intermittent 9.3%, P < 0.001), with weight loss of ≥ 2 kg (OR 2.5-5.1, weight loss 22.1%, without weight loss 6.4%, P < 0.0005) and without reflux (OR 1.2-2.5, reflux 7.2%, no reflux 15.5%, P < 0.0005). The likelihood of malignancy was greater in those who described true dysphagia (food or drink sticking within 5 s of swallowing than those who did not (15.1% vs 5.2% respectively, P < 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the EDS were 98.4%, 9.3%, 11.8% and 98.0% respectively. Three patients with an EDS of 3 (high risk EDS ≥ 3.5) had malignancy. Unlike the original validation cohort, there was no difference in likelihood of malignancy based on level of dysphagia (pharyngeal level dysphagia 11.9% vs mid sternal or lower sternal dysphagia 12.4%). Peptic stricture was statistically more frequent in those with longer duration of symptoms (> 6 mo, OR 1.2-2.9, ≤ 8 wk 9.8%, 8-26 wk 10.6%, > 26 wk 15.7%, P < 0.05) and over 60 s (OR 1.2-3.0, age < 60 years 6.2%, 60-73 years 10.2%, > 73 years 10.6%, P < 0.05).
CONCLUSION: Malignancy and peptic stricture are frequent findings in those referred with dysphagia. The predictive value for associated features could help determine need for fast track investigation whilst reducing service pressures.

Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall TR1 3LJ

Bye H, Prescott NJ, Lewis CM, et al.
Distinct genetic association at the PLCE1 locus with oesophageal squamous cell carcinoma in the South African population.
Carcinogenesis. 2012; 33(11):2155-61 [PubMed] Article available free on PMC after 01/11/2013

Oesophageal squamous cell carcinoma (OSCC) has a high prevalence in the Black and Mixed Ancestry populations of South Africa. Recently, three genome-wide association studies in Chinese populations identified five new OSCC susceptibility loci, including variants at PLCE1, C20orf54, PDE4D, RUNX1 and UNC5CL, but their contribution to disease risk in other populations is unknown. In this study, we report testing variants from these five loci for association with OSCC in the South African Black (407 cases and 849 controls) and Mixed Ancestry (257 cases and 860 controls) populations. The RUNX1 variant rs2014300, which reduced risk in the Chinese population, was associated with an increased risk of OSCC in the Mixed Ancestry population [odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.09-1.63, P = 0.0055], and none of the five loci were associated in the Black population. Since PLCE1 variants increased the risk of OSCC in all three Chinese studies, this gene was investigated further by sequencing in 46 Black South Africans. This revealed 48 variants, 10 of which resulted in amino acid substitutions, and much lower linkage disequilibrium across the PLCE1 locus than in the Chinese population. We genotyped five PLCE1 variants in cases and controls, and found association of Arg548Leu (rs17417407) with a reduced risk of OSCC (OR = 0.74, 95% CI = 0.60-0.93, P = 0.008) in the Black population. These findings indicate several differences in the genetic contribution to OSCC between the South African and Chinese populations that may be related to differences in their genetic architecture.

Department of Medical and Molecular Genetics, King's College London, King's Health Partners, Guy's Hospital, London

Preston SR, Baker CR, Priest OH, Sudderick RM
Thoracoscopic-assisted four-phase esophagectomy with four-field lymph node dissection for esophageal cancer: case report and description of a new technique.
J Laparoendosc Adv Surg Tech A. 2012; 22(7):701-4 [PubMed]

Complete (R0) resection and extent of lymphadenectomy are important prognostic factors for survival in patients undergoing surgery for esophageal carcinoma. We describe the first case of combined open and thoracoscopic esophagectomy with extended lymphadenectomy including abdominal, cervical, right, and left mediastinal (four-field, four-phase) nodal clearance in a 37-year-old woman with squamous cell carcinoma of the esophagus. This report provides a tailored strategy to achieve a high level of tumor clearance and complete resection. The approach described challenges the limitations of standard radical nodal clearance and may encourage surgeons to consider more extensive resections.

The Regional Oesophago-Gastric Unit, Royal Surrey County Hospital, Guildford

Milind R, Attwood SE
Natural history of Barrett's esophagus.
World J Gastroenterol. 2012; 18(27):3483-91 [PubMed] Article available free on PMC after 01/11/2013

The natural history of Barrett's esophagus (BE) is difficult to quantify because, by definition, it should describe the course of the condition if left untreated. Pragmatically, we assume that patients with BE will receive symptomatic treatment with acid suppression, usually a proton pump inhibitor, to treat their heartburn. This paper describes the development of complications of stricture, ulcer, dysplasia and adenocarcinoma from this standpoint. Controversies over the definition of BE and its implications in clinical practice are presented. The presence of intestinal metaplasia and its relevance to cancer risk is discussed, and the need to measure the extent of the Barrett's epithelium (long and short segments) using the Prague guidelines is emphasized. Guidelines and international consensus over the diagnosis and management of BE are being regularly updated. The need for expert consensus is important due to the lack of randomized trials in this area. After searching the literature, we have tried to collate the important studies regarding progression of Barrett's to dysplasia and adenocarcinoma. No therapeutic studies yet reported show a clear reduction in the development of cancer in BE. The effect of pharmacological and surgical intervention on the natural history of Barrett's is a subject of ongoing research, including the Barrett's Oesophagus Surveillance Study and the aspirin and esomeprazole cancer chemoprevention trial with interesting results. The geographical variation and the wide range of outcomes highlight the difficulty of providing an individualized risk profile to patients with BE. Future studies on the interaction of genome wide abnormalities in Barrett's and their interaction with environmental factors may allow individualization of the risk of cancer developing in BE.

Department of Surgery, North Tyneside General Hospital, North Shields, Tyne and Wear NE29 8NH

Bird-Lieberman EL, Dunn JM, Coleman HG, et al.
Population-based study reveals new risk-stratification biomarker panel for Barrett's esophagus.
Gastroenterology. 2012; 143(4):927-35.e3 [PubMed]

BACKGROUND & AIMS: The risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is low and difficult to calculate. Accurate tools to determine risk are needed to optimize surveillance and intervention. We assessed the ability of candidate biomarkers to predict which cases of BE will progress to EAC or high-grade dysplasia and identified those that can be measured in formalin-fixed tissues.
METHODS: We analyzed data from a nested case-control study performed using the population-based Northern Ireland BE Register (1993-2005). Cases who progressed to EAC (n = 89) or high-grade dysplasia ≥ 6 months after diagnosis with BE were matched to controls (nonprogressors, n = 291), for age, sex, and year of BE diagnosis. Established biomarkers (abnormal DNA content, p53, and cyclin A expression) and new biomarkers (levels of sialyl Lewis(a), Lewis(x), and Aspergillus oryzae lectin [AOL] and binding of wheat germ agglutinin) were assessed in paraffin-embedded tissue samples from patients with a first diagnosis of BE. Conditional logistic regression analysis was applied to assess odds of progression for patients with dysplastic and nondysplastic BE, based on biomarker status.
RESULTS: Low-grade dysplasia and all biomarkers tested, other than Lewis(x), were associated with risk of EAC or high-grade dysplasia. In backward selection, a panel comprising low-grade dysplasia, abnormal DNA ploidy, and AOL most accurately identified progressors and nonprogressors. The adjusted odds ratio for progression of patients with BE with low-grade dysplasia was 3.74 (95% confidence interval, 2.43-5.79) for each additional biomarker and the risk increased by 2.99 for each additional factor (95% confidence interval, 1.72-5.20) in patients without dysplasia.
CONCLUSIONS: Low-grade dysplasia, abnormal DNA ploidy, and AOL can be used to identify patients with BE most likely to develop EAC or high-grade dysplasia.

Medical Research Council Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge

di Pietro M, Lao-Sirieix P, Boyle S, et al.
Evidence for a functional role of epigenetically regulated midcluster HOXB genes in the development of Barrett esophagus.
Proc Natl Acad Sci U S A. 2012; 109(23):9077-82 [PubMed] Article available free on PMC after 01/11/2013

Barrett esophagus (BE) is a human metaplastic condition that is the only known precursor to esophageal adenocarcinoma. BE is characterized by a posterior intestinal-like phenotype in an anterior organ and therefore it is reminiscent of homeotic transformations, which can occur in transgenic animal models during embryonic development as a consequence of mutations in HOX genes. In humans, acquired deregulation of HOX genes during adulthood has been linked to carcinogenesis; however, little is known about their role in the pathogenesis of premalignant conditions. We hypothesized that HOX genes may be implicated in the development of BE. We demonstrated that three midcluster HOXB genes (HOXB5, HOXB6, and HOXB7) are overexpressed in BE, compared with the anatomically adjacent normal esophagus and gastric cardia. The midcluster HOXB gene signature in BE is identical to that seen in normal colonic epithelium. Ectopic expression of these three genes in normal squamous esophageal cells in vitro induces markers of intestinal differentiation, such as KRT20, MUC2, and VILLIN. In BE-associated adenocarcinoma, the activation midcluster HOXB gene is associated with loss of H3K27me3 and gain of AcH3, compared with normal esophagus. These changes in histone posttranslational modifications correlate with specific chromatin decompaction at the HOXB locus. We suggest that epigenetically regulated alterations of HOX gene expression can trigger changes in the transcriptional program of adult esophageal cells, with implications for the early stages of carcinogenesis.

Medical Research Council Cancer Cell Unit, Hutchison Medical Research Council Research Centre, CB2 0XZ Cambridge

Fareed KR, Soomro IN, Hameed K, et al.
Caspase-cleaved cytokeratin-18 and tumour regression in gastro-oesophageal adenocarcinomas treated with neoadjuvant chemotherapy.
World J Gastroenterol. 2012; 18(16):1915-20 [PubMed] Article available free on PMC after 01/11/2013

AIM: To examine cytokeratin-18 (CK-18) and caspase-cleaved CK-18 expression in tumours and correlate with clinicopathological outcomes including tumour regression grade (TRG) response.
METHODS: Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays. The first set consisted of 122 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 97 gastric/gastro-oesophageal cancer cases exposed to pre-operative platinum-based chemotherapy. Expression of CK-18 and caspase-cleaved CK-18 was investigated using immunohistochemistry.
RESULTS: CK18 was commonly expressed in gastro-oesophageal tumours (92.6%). Fifty-six point seven percent of tumours previously exposed to neoadjuvant chemotherapy were positive for caspase-cleaved CK-18 expression compared to only 24.6% of tumours not previously exposed to neoadjuvant chemotherapy (P = 0.009). In patients who received neoadjuvant chemotherapy, caspase-cleaved cytokeratin-18 expression correlated with favourable TRG response (TRG 1, 2 or 3, P = 0.043).
CONCLUSION: This is the largest study to date of CK-18 and caspase-cleaved CK-18 expression in gastro-oesophageal tumours. We provide the first evidence that caspase-cleaved CK-18 predicts tumour regression with neoadjuvant chemotherapy.

Laboratory of Molecular Oncology, Academic Unit of Oncology, School of Molecular Medical Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham University Hospitals, Nottingham NG5 1PB

Noble F, Curtis N, Harris S, et al.
Risk assessment using a novel score to predict anastomotic leak and major complications after oesophageal resection.
J Gastrointest Surg. 2012; 16(6):1083-95 [PubMed]

BACKGROUND: Oesophagectomy is associated with significant morbidity and mortality. A simple score to define a patient's risk of developing major complications would be beneficial.
METHODS: Patients who underwent upper gastrointestinal resections with an oesophageal anastomosis between 2005 and 2010 were reviewed and formed the development dataset with resections performed in 2011 forming a prospective validation dataset. The association between post-operative C-reactive protein (CRP), white cell count (WCC) and albumin levels with anastomotic leak (AL) or major complication including death using the Clavien-Dindo (CD) classification were analysed by receiver operating characteristic curves. After multivariate analysis, from the development dataset, these factors were combined to create a novel score which was subsequently tested on the validation dataset.
RESULTS: Two hundred fifty-eight patients were assessed to develop the score. Sixty-three patients (25%) developed a major complication, and there were seven (2.7%) in-patient deaths. Twenty-six (10%) patients were diagnosed with AL at median post-operative day 7 (range: 5-15). CRP (p = 0.002), WCC (p < 0.0001) and albumin (p = 0.001) were predictors of AL. Combining these markers improved prediction of AL (NUn score > 10: sensitivity 95%, specificity 49%, diagnostic accuracy 0.801 (95% confidence interval: 0.692-0.909, p < 0.0001)). The validation dataset confirmed these findings (NUn score > 10: sensitivity 100%, specificity 57%, diagnostic accuracy 0.879 (95% CI 0.763-0.994, p = 0.014)) and a major complication or death (NUn > 10: sensitivity 89%, specificity 63%, diagnostic accuracy 0.856 (95% CI 0.709-1, p = 0.001)).
CONCLUSIONS: Blood-borne markers of the systemic inflammatory response are predictors of AL and major complications after oesophageal resection. When combined they may categorise a patient's risk of developing a serious complication with higher sensitivity and specificity.

Department of Surgery, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, Hampshire, SO16 6YD

Paterson S, Duthie F, Stanley AJ
Endoscopic ultrasound-guided elastography in the nodal staging of oesophageal cancer.
World J Gastroenterol. 2012; 18(9):889-95 [PubMed] Article available free on PMC after 01/11/2013

AIM: To assess quantitative endoscopic ultrasound (EUS)-guided elastography in the nodal staging of oesophago-gastric cancers.
METHODS: This was a single tertiary centre study assessing 50 patients with established oesophago-gastric cancer undergoing EUS-guided fine needle aspiration biopsy (FNAB) of lymph nodes between July 2007 and July 2009. EUS-guided elastography of lymph nodes was performed before EUS-FNAB. Standard EUS characteristics were also described. Cytological determination of whether a lymph node was malignant or benign was used as the gold standard for this study. Comparisons of elastography and standard EUS characteristics were made between the cytologically benign and malignant nodes. The main outcome measure was the accuracy of elastography in differentiating between benign and malignant lymph nodes in oesophageal cancers.
RESULTS: EUS elastography and FNAB were performed on 53 lymph nodes. Cytological malignancy was found in 23 nodes, one was indeterminate, one was found to be a gastrointestinal stromal tumor and 25 of the nodes were negative for malignancy. On 3 occasions insufficient material was obtained for analysis. The area under the curve for the receiver operating characteristic curve for elastography strain ratio was 0.87 (P < 0.0001). Elastography strain ratio had a sensitivity 83%, specificity 96%, positive predictive value 95%, and negative predictive value 86% for distinguishing between malignant and benign nodes. The overall accuracy of elastography strain ratio was 90%. Elastography was more sensitive and specific in determining malignant nodal disease than standard EUS criteria.
CONCLUSION: EUS elastography is a promising modality that may complement standard EUS and help guide EUS-FNAB during staging of upper gastrointestinal tract cancer.

Department of Gastroenterology, Forth Valley Royal Hospital, Larbert FK5 4WR

McRonald FE, Risk JM, Hodges NJ
Protection from intracellular oxidative stress by cytoglobin in normal and cancerous oesophageal cells.
PLoS One. 2012; 7(2):e30587 [PubMed] Article available free on PMC after 01/11/2013

Cytoglobin is an intracellular globin of unknown function that is expressed mostly in cells of a myofibroblast lineage. Possible functions of cytoglobin include buffering of intracellular oxygen and detoxification of reactive oxygen species. Previous work in our laboratory has demonstrated that cytoglobin affords protection from oxidant-induced DNA damage when over expressed in vitro, but the importance of this in more physiologically relevant models of disease is unknown. Cytoglobin is a candidate for the tylosis with oesophageal cancer gene, and its expression is strongly down-regulated in non-cancerous oesophageal biopsies from patients with TOC compared with normal biopsies. Therefore, oesophageal cells provide an ideal experimental model to test our hypothesis that downregulation of cytoglobin expression sensitises cells to the damaging effects of reactive oxygen species, particularly oxidative DNA damage, and that this could potentially contribute to the TOC phenotype. In the current study, we tested this hypothesis by manipulating cytoglobin expression in both normal and oesophageal cancer cell lines, which have normal physiological and no expression of cytoglobin respectively. Our results show that, in agreement with previous findings, over expression of cytoglobin in cancer cell lines afforded protection from chemically-induced oxidative stress but this was only observed at non-physiological concentrations of cytoglobin. In addition, down regulation of cytoglobin in normal oesophageal cells had no effect on their sensitivity to oxidative stress as assessed by a number of end points. We therefore conclude that normal physiological concentrations of cytoglobin do not offer cytoprotection from reactive oxygen species, at least in the current experimental model.

School of Biosciences, The University of Birmingham, Edgbaston, Birmingham

O'Rorke MA, Cantwell MM, Abnet CC, et al.
Toenail trace element status and risk of Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
Int J Cancer. 2012; 131(8):1882-91 [PubMed] Article available free on PMC after 15/10/2013

Trace elements have been cited as both inhibitory and causative agents of cancer but importantly exposure to them is potentially modifiable. Our study aimed to examine toenail trace element status and risk of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Toenail clippings from each hallux were obtained from 638 participants of the FINBAR (Factors Influencing the Barrett's Adenocarcinoma Relationship) study comprising 221 healthy controls, 98 reflux oesophagitis, 182 BO and 137 OAC cases. The concentrations of eight toenail trace elements were determined using instrumental neutron activation analysis. Using multivariable adjusted logistic regression analysis, odds ratios (OR) and 95% confidence intervals (CIs) were calculated within tertiles of trace element concentrations. A twofold increased risk of BO was observed, but not OAC, among individuals in the highest tertile of toenail zinc status OR 2.21 (95% CI, 1.11-4.40). A higher toenail selenium status was not associated with risk of OAC OR 0.94 (95% CI, 0.44-2.04) or BO OR 0.89 (95% CI, 0.37-2.12). A borderline significant increased risk of BO was detected with a higher toenail cobalt concentration, OR 1.97 (95% CI, 1.01-3.85). No association was found between toenail levels of chromium, cerium, mercury and OAC or BO risk. This is the first case-control study to investigate a variety of trace elements in relation to OAC and BO risk. Despite antioxidant and proapoptotic properties, no associations were found with selenium. Higher concentrations of toenail zinc and cobalt were associated with an increased BO risk, but not OAC. These findings need confirmation in prospective analysis.

Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queens University Belfast, Institute of Clinical Sciences Block B, Belfast

Mamidanna R, Bottle A, Aylin P, et al.
Short-term outcomes following open versus minimally invasive esophagectomy for cancer in England: a population-based national study.
Ann Surg. 2012; 255(2):197-203 [PubMed]

OBJECTIVE: To compare short-term outcomes of open and minimally invasive esophagectomy (MIE) for cancer.
BACKGROUND DATA: Numerous studies have demonstrated the safety and possible advantages of MIE in selected cohorts of patients. The increasing use of MIE is not coupled with conclusive evidence of its benefits over "open" esophagectomy, especially in the absence of randomized trials.
METHODS: Hospital Episode Statistics data were analyzed from April 2005 to March 2010. This is a routinely collected database of all English National Health Service Trusts. Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures, 4th revision (OPCS-4), procedure codes were used to identify index resections and International Statistical Classification of Diseases, 10th Revision (ICD-10), diagnostic codes were used to ascertain comorbidity status and complications. Thirty-day in-hospital mortality, medical complications, and surgical reinterventions were analyzed. Unadjusted and risk-adjusted regression analyses were undertaken.
RESULTS: Seven thousand five hundred and two esophagectomies were undertaken; of these, 1155 (15.4%) were MIE. In 2009-2010, 24.7% of resections were MIE. There was no difference in 30-day mortality (4.3% vs 4.0%; P = 0.605) and overall medical morbidity (38.0% vs 39.2%; P = 0.457) rates between open and MIE groups, respectively. A higher reintervention rate was associated with the MIE group than with the open group (21% vs 17.6%, P = 0.006; odds ratio, 1.17; 95% confidence interval, 1.00-1.38; P = 0.040).
CONCLUSIONS: Minimally invasive esophagectomy is increasingly performed in the United Kingdom. Although the study confirmed the safety of MIE in a population-based national data, there are no significant benefits demonstrated in mortality and overall morbidity. Minimally invasive esophagectomy is associated with higher reintervention rate. Further evidence is needed to establish the long-term survival of MIE.

Department of Surgery and Cancer, St Mary's Hospital, Imperial College London

Suttie SA, Nanthakumaran S, Mofidi R, et al.
The impact of operative approach for oesophageal cancer on outcome: the transhiatal approach may influence circumferential margin involvement.
Eur J Surg Oncol. 2012; 38(2):157-65 [PubMed]

AIM: Surgery for oesophageal cancer remains the only means of cure for invasive tumours. It is claimed that the surgical approach for these cancers impacts on morbidity and may influence the ability to achieve tumour clearance and therefore survival, however there is no conclusive evidence to support one approach over another. This study aims to determine the impact of operative approach on tumour margin involvement and survival.
METHODS: Data were extracted from the Scottish Audit of Gastric and Oesophageal Cancer (SAGOC), a prospective population-based audit of all oesophageal and gastric cancers in Scotland between 1997 and 1999 with a minimum of five-year follow up. Analysis focused on the three commonest approaches (Ivor Lewis n = 140, transhiatal n = 68, left thoraco-laparotomy n = 142) for oesophageal cancer.
RESULTS: Operative approach had no significant impact on post-operative morbidity, mortality, overall margin involvement and survival. Transhiatal approach resulted in significantly more circumferential margin involvement (p = 0.019), and the presence of circumferential margin involvement significantly reduced five-year survival (median survival 13 months) compared to no margin involvement (median survival 25 months, p = 0.001).
CONCLUSION: Surgical approach for oesophageal cancer had no significant effect on morbidity, post-operative mortality and five-year survival. Non-selective use of the transhiatal approach is associated with a significantly greater circumferential margin involvement, with positive circumferential margin impacting adversely on 5-year survival.

Department of Surgery and Molecular Oncology, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland

McGrath EE, Warriner D, Anderson P
The insertion of self expanding metal stents with flexible bronchoscopy under sedation for malignant tracheobronchial stenosis: a single-center retrospective analysis.
Arch Bronconeumol. 2012; 48(2):43-8 [PubMed]

OBJECTIVE: To describe a 10-year experience of inserting Ultraflex™ self-expanding metal stents (SEMS) under sedation using flexible bronchoscopy for the treatment of malignant tracheobronchial stenosis in a tertiary referral centre.
METHODS: Medical notes were retrospectively reviewed for all patients who underwent SEMS insertion between 1999 and 2009.
RESULTS: A data analysis of 68 patients who had Ultraflex™ SEMS inserted under sedation was completed. Thirty three males and 35 females with a mean age of 67.9 years (range 35-94) presented with features including dyspnea/respiratory distress (39 patients), stridor (16 patients) and hemoptysis/dyspnea (13 patients). Etiology of stenosis included lung cancer (46 patients) esophageal cancer (14 patients) and other malignancies (8 patients). Mean dose of midazolam administered was 5mg (range 0-10mg). The trachea was the most common site of stent insertion followed by the right and left main bronchus, respectively. Adjuvant laser therapy was applied at some stage in 31% of all cases, and chemotherapy and/or radiotherapy was administered to at least 64% of patients with malignant disease. Hemoptysis and stent migration were the most frequent complications (5 and 4 patients, respectively). The mean survival time of stented non-small cell lung cancer (NSCLC) patients was 214 days (range 5-1233) and that of esophageal malignancy was 70 days (range 12-249). Mean pack-year history of individuals with lung cancer requiring stent insertion was 37 (range 2-100).
CONCLUSION: Ultraflex stents offer a safe and effective therapy for patients who are inoperable or unresectable that otherwise would have no alternative therapy. It has an immediate beneficial effect upon patients, not only through symptom relief but, in some, through prolongation of life. Survival data is no worse than other studies using different varieties of stents and insertion techniques indicating its longer-term efficacy. Moreover, this report highlights the feasibility of performing this procedure successfully in a respiratory unit, without the need for general anesthesia.

Department of Respiratory Medicine, Northern General Hospital, Sheffield

O'Doherty MG, Freedman ND, Hollenbeck AR, et al.
Association of dietary fat intakes with risk of esophageal and gastric cancer in the NIH-AARP diet and health study.
Int J Cancer. 2012; 131(6):1376-87 [PubMed] Article available free on PMC after 15/09/2013

The aim of our study was to investigate whether intakes of total fat and fat subtypes were associated with esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastric cardia or gastric noncardia adenocarcinoma. From 1995-1996, dietary intake data was reported by 494,978 participants of the NIH-AARP cohort. The 630 EAC, 215 ESCC, 454 gastric cardia and 501 gastric noncardia adenocarcinomas accrued to the cohort. Cox proportional hazards regression was used to examine the association between the dietary fat intakes, whilst adjusting for potential confounders. Although apparent associations were observed in energy-adjusted models, multivariate adjustment attenuated results to null [e.g., EAC energy adjusted hazard ratio (HR) and 95% confidence interval (95% CI) 1.66 (1.27-2.18) p for trend <0.01; EAC multivariate adjusted HR (95% CI) 1.17 (0.84-1.64) p for trend = 0.58]. Similar patterns were also observed for fat subtypes [e.g., EAC saturated fat, energy adjusted HR (95% CI) 1.79 (1.37-2.33) p for trend <0.01; EAC saturated fat, multivariate adjusted HR (95% CI) 1.27 (0.91-1.78) p for trend = 0.28]. However, in multivariate models an inverse association for polyunsaturated fat (continuous) was seen for EAC in subjects with a body mass index (BMI) in the normal range (18.5-<25 kg/m(2)) [HR (95% CI) 0.76 (0.63-0.92)], that was not present in overweight subjects [HR (95% CI) 1.04 (0.96-1.14)], or in unstratified analysis [HR (95% CI) 0.97 (0.90-1.05)]. p for interaction = 0.02. Overall, we found null associations between the dietary fat intakes with esophageal or gastric cancer risk; although a protective effect of polyunsaturated fat intake was seen for EAC in subjects with a normal BMI.

Cancer Epidemiology Health Services Research Group, Centre for Public Health, Queens University Belfast, Belfast, Northern Ireland

Griffin SM, Burt AD, Jennings NA
Lymph node metastasis in early esophageal adenocarcinoma.
Ann Surg. 2011; 254(5):731-6; discussion 736-7 [PubMed]

OBJECTIVE: To accurately document the incidence of lymph node metastases (LNM) in early esophageal adenocarcinoma with regard to the depth of invasion of the mucosa or submucosa.
BACKGROUND: Endoscopic therapy is now being proposed as a viable treatment for submucosal esophageal adenocarcinoma. If such treatments are appropriate, then the risk of LNM must be shown to be low in these tumors.
METHODS: One hundred nineteen consecutive patients underwent radical esophagectomy alone for treatment of superficial esophageal adenocarcinoma or high-grade dysplasia. The resection specimens were analyzed by an expert gastrointestinal pathologist and the presence of LNM and the depth of tumor invasion were recorded. Depth of invasion was classified as either confined to the mucosa, the first third of the submucosa, the middle third of the submucosa, or the final third of the submucosa.
RESULTS: Fifty-four patients had high-grade dysplasia or tumors confined to the mucosa with no evidence of LNM (0/54, 0%), 65 patients had tumor invading the submucosa with 8 patients having LNM (8/65, 12%). Subclassification of submucosal invasion showed that 5 of 22 "first third of the submucosa" tumors had LNM (23%), 1 of 24 "middle third of the submucosa" tumors had LNM (4%), and 2 of 19 "final third of the submucosa" tumors had LNM (11%).
CONCLUSION: Invasion of the submucosa is associated with significant risk of LNM. Patients with submucosal invasion are not suitable for endoscopic treatment and surgical resection remains the gold standard treatment for patients with submucosal adenocarcinoma who are fit to undergo the procedure.

Northern Oesophago-Gastric Cancer Unit, Royal Victoria Infirmary, Newcastle upon Tyne

Wiseman EF, Ang YS
Risk factors for neoplastic progression in Barrett's esophagus.
World J Gastroenterol. 2011; 17(32):3672-83 [PubMed] Article available free on PMC after 15/09/2013

Barrett's esophagus (BE) confers a significant increased risk for development of esophageal adenocarcinoma (EAC), with the pathogenesis appearing to progress through a "metaplasia-dysplasia-carcinoma" (MDC) sequence. Many of the genetic insults driving this MDC sequence have recently been characterized, providing targets for candidate biomarkers with potential clinical utility to stratify risk in individual patients. Many clinical risk factors have been investigated, and associations with a variety of genetic, specific gastrointestinal and other modifiable factors have been proposed in the literature. This review summarizes the current understanding of the mechanisms involved in neoplastic progression of BE to EAC and critically appraises the relative roles and contributions of these putative risk factors from the published evidence currently available.

Department of Gastroenterology, Royal Albert Edward Infirmary, Wigan Lane, Wigan, Greater Manchester WN12NN

Gujral DM, Hawkins MA, Leonulli BG, et al.
Nonsurgical management of esophageal adenocarcinoma.
Clin Colorectal Cancer. 2011; 10(3):165-70 [PubMed]

BACKGROUND: The benefit of induction chemotherapy (IC) before chemoradiotherapy (CRT) for inoperable esophageal adenocarcinoma has not been established. To clarify toxicities and outcomes of combined modality treatment, we performed a retrospective review.
MATERIALS AND METHODS: Sixty-eight consecutive patients were identified. Fifty-one patients had CRT, 17 had radiotherapy (RT). Fifty-eight received IC before RT. IC consisted of 4 cycles of platinum and fluoropyrimidines followed by CRT 54 Gy with concurrent infusional 5-fluorouracil (5-FU) or capecitabine. Response to IC was assessed at 3 months and response to CRT at 3 months. Time to progression (TTP) and overall survival (OS) are reported.
RESULTS: Fifty-four patients were men and 14 were women, with median age 72 years (range, 42-87 years). There were 29 stage II, 33 stage III, 4 stage IVa, and 2 stage IVb tumors. The response 3 months after completion of treatment was 39.6%. No grade 4 toxicity was reported, but 10/58 patients had grade 3 toxicity from IC. The median TTP and OS from RT for the entire cohort was 12 months (95% confidence interval [CI], 7-18) and 16 months (95% CI, 5-27), respectively. The 1- and 2-year survival rates from diagnosis were 73% and 47%, respectively. There was no statistically significant difference in TTP or OS in patients who responded to IC compared with those who did not (median TTP 11 vs. 12 months, respectively; P = .8; median OS 15 vs. 14 months, respectively; P = .8).
CONCLUSION: The outcome in patients with adenocarcinoma of the esophagus after CRT is comparable to unselected surgical series. Response to IC is not always an indicator of eventual outcome.

Gastrointestinal Unit, Royal Marsden Hospital NHS Foundation Trust, Sutton

Yuen HF, McCrudden CM, Chan KK, et al.
The role of Pea3 group transcription factors in esophageal squamous cell carcinoma.
Am J Pathol. 2011; 179(2):992-1003 [PubMed] Article available free on PMC after 15/09/2013

The transcription factors Pea3, Erm, and Er81 can promote cancer initiation and progression in various types of solid tumors. However, their role in esophageal squamous cell carcinoma (ESCC) has not been elucidated. In this study, we found that the expression levels of Pea3 and Erm, but not that of Er81, were significantly higher in ESCC compared with nontumor esophageal epithelium. A high level of Pea3 expression was significantly correlated with a shorter overall survival in a cohort of 81 patients with ESCC and the subgroup with N1 stage tumor (Wilcoxon-Gehan test, P = 0.016 and P = 0.001, respectively). Pea3 was overexpressed in seven ESCC cell lines compared with two immortalized esophageal cell lines. Pea3 knockdown reduced cell proliferation and suppressed nonadherent growth, migration, and invasion in ESCC cells in vitro. In addition, Pea3 knockdown in ESCC cells resulted in a down-regulation of phospho-Akt and matrix metalloproteinase 13, whereas a significant positive correlation in the expression levels was observed between Pea3 and phospho-Akt (r = 0.281, P < 0.013) and between Pea3 and matrix metalloproteinase 13 in the human specimens (r = 0.462, P < 0.001). Moreover, Pea3 modulated the sensitivity of EC109 cells to doxorubicin, probably via reduced activity of the phosphatidylinositol 3-kinase-Akt-mammalian target of Rapamycin complex 1 pathway on Pea3 knockdown. In conclusion, our results suggest that Pea3 plays an important role in the progression of ESCC.

Center for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast

Pink RC, Bailey TA, Iputo JE, et al.
Molecular basis for maize as a risk factor for esophageal cancer in a South African population via a prostaglandin E2 positive feedback mechanism.
Nutr Cancer. 2011; 63(5):714-21 [PubMed]

The incidence of squamous cancer of the esophagus varies up to a hundredfold in different regions of the world. In Transkei, South Africa, a particularly high incidence of the disease is observed. We have previously proposed an association between a maize-rich diet and elevated levels of intragastric prostaglandin E2 production (PGE(2)). Here we investigate the molecular mechanisms by which a high-maize diet could lead to increased incidence of squamous cancer of the esophagus. We confirm that levels of PGE(2) are high (606.8 pg/ml) in the gastric fluid of individuals from Transkei. We also show that treatment of esophageal cells with linoleic acid, which is found at high levels in maize and is a precursor to PGE(2), leads to increased cell proliferation. Similarly, treatment of cells with PGE(2) or with gastric fluid from Transkeians also leads to increased proliferation. Our data suggest that the high levels of PGE(2) associated with a maize-rich diet stimulate cell division and induce the enzyme COX 2, resulting in a positive feedback mechanism that predisposes the esophagus to carcinoma.

Cranfield Health, Cranfield University, Cranfield, Bedfordshire

Smart H, Kia R, Subramanian S, et al.
Defining the endoscopic appearances of tylosis using conventional and narrow-band imaging: a case series.
Endoscopy. 2011; 43(8):727-30 [PubMed]

Tylosis is an autosomal dominant skin disorder strongly associated with esophageal squamous cell cancer. We present a single-operator experience of utilizing conventional endoscopy and narrow-band imaging with magnification to characterize esophageal appearances in tylosis. Nineteen consecutive patients with tylosis attending for surveillance endoscopy were studied. White-light imaging (WLI) and narrow-band imaging (NBI) were undertaken, with magnification being performed as necessary. On WLI, we classified 12 patients as having mild change, 5 moderate change, and 2 severe change. WLI can define changes to the esophageal mucosa of variable hyperkeratosis and identify more significant focal abnormalities. NBI enhances these mucosal changes, and NBI with magnification can demonstrate intrapapillary capillary loop changes compatible with dysplasia, prompting consideration of surgery. This report is the first to characterize the endoscopic appearances in tylosis.

Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool

O'Doherty MG, Cantwell MM, Murray LJ, et al.
Dietary fat and meat intakes and risk of reflux esophagitis, Barrett's esophagus and esophageal adenocarcinoma.
Int J Cancer. 2011; 129(6):1493-502 [PubMed] Article available free on PMC after 15/09/2013

The aim of our study was to investigate whether dietary fat and meat intakes are associated with reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). In this all-Ireland case-control study, dietary intake data were collected using a food frequency questionnaire in 219 RE patients, 220 BE patients, 224 EAC patients and 256 frequency-matched controls between 2002 and 2005. Unconditional multiple logistic regression analysis was used to examine the association between dietary variables and disease risk using quartiles of intake, to attain odds ratios (ORs) and 95% confidence intervals (95% CIs), while adjusting for potential confounders. Patients in the highest quartile of total fat intake had a higher risk of RE (OR = 3.54; 95% CI = 1.32-9.46) and EAC (OR = 5.44; 95% CI = 2.08-14.27). A higher risk of RE and EAC was also reported for patients in the highest quartile of saturated fat intake (OR = 2.79; 95% CI = 1.11-7.04; OR = 2.41; 95% CI = 1.14-5.08, respectively) and monounsaturated fat intake (OR = 2.63; 95% CI = 1.01-6.86; OR = 5.35; 95% CI = 2.14-13.34, respectively). Patients in the highest quartile of fresh red meat intake had a higher risk of EAC (OR = 3.15; 95% CI = 1.38-7.20). Patients in the highest category of processed meat intake had a higher risk of RE (OR = 4.67; 95% CI = 1.71-12.74). No consistent associations were seen for BE with either fat or meat intakes. Further studies investigating the association between dietary fat and food sources of fat are needed to confirm these results.

Cancer Epidemiology Health Services Research Group, Centre for Public Health, Queens University Belfast, Belfast, Northern Ireland

Feber A, Xi L, Pennathur A, et al.
MicroRNA prognostic signature for nodal metastases and survival in esophageal adenocarcinoma.
Ann Thorac Surg. 2011; 91(5):1523-30 [PubMed] Article available free on PMC after 15/09/2013

BACKGROUND: The incidence of esophageal adenocarcinoma is rapidly increasing and is now one of the leading causes of cancer death in the western world. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of protein-encoding genes and are involved in the development, progression and prognosis of other malignancies. We hypothesized that global miRNA expression would predict survival and lymph node involvement in a cohort of surgically resected esophagus cancer patients.
METHODS: The miRNA analysis was performed using a custom Affymetrix microarray with probes for 462 known human, 2,102 predicted human, 357 mouse, and 238 rat miRNAs. Expression of miRNA was evaluated in 45 primary tumors, and the association of miRNA expression with patient survival and lymph node metastasis was assessed. The prognostic impact of identified unique miRNAs was verified with quantitative reverse transcriptase polymerase chain reaction.
RESULTS: Our data indicate that the expression of individual human miRNA species is significantly associated with postresection patient survival. Using data from five unique miRNAs, we were further able to generate a combined miRNA expression signature that is associated with patient survival (p=0.005; hazard ratio 3.6) independent of node involvement and overall stage. The expression of three miRNAs (miR-99b and miR-199a_3p and _5p) was also associated with the presence of lymph node metastasis.
CONCLUSIONS: These results suggest miRNA expression profiling could provide prognostic utility in staging esophagus cancer patients and treatment planning with endoscopic and neoadjuvant therapies. The alterations of specific miRNAs may further elucidate steps in the metastatic pathway and allow for development of targeted therapy.

University College London, Cancer Institute, London

Ong CA, Lao-Sirieix P, Fitzgerald RC
Biomarkers in Barrett's esophagus and esophageal adenocarcinoma: predictors of progression and prognosis.
World J Gastroenterol. 2010; 16(45):5669-81 [PubMed] Article available free on PMC after 15/09/2013

Barrett's esophagus is a well-known premalignant lesion of the lower esophagus that is characterized by intestinal metaplasia of the squamous epithelium. It is clinically important due to the increased risk (0.5% per annum) of progression to esophageal adenocarcinoma (EA), which has a poor outcome unless diagnosed early. The current clinical management of Barrett's esophagus is hampered by the lack of accurate predictors of progression. In addition, when patients develop EA, the current staging modalities are limited in stratifying patients into different prognostic groups in order to guide the optimal therapy for an individual patient. Biomarkers have the potential to improve radically the clinical management of patients with Barrett's esophagus and EA but have not yet entered mainstream clinical practice. This is in contrast to other cancers like breast and prostate for which biomarkers are utilized routinely to inform clinical decisions. This review aims to highlight the most promising predictive and prognostic biomarkers in Barrett's esophagus and EA and to discuss what is required to move the field forward towards clinical application.

MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Box 197/ Hills Road, Cambridge, CB20XZ

Yakoub D, Keun HC, Goldin R, Hanna GB
Metabolic profiling detects field effects in nondysplastic tissue from esophageal cancer patients.
Cancer Res. 2010; 70(22):9129-36 [PubMed]

The variable rate of missed cancer in endoscopic biopsies and lack of other biomarkers reduce the effectiveness of surveillance programs in esophageal cancer. Based on the "field cancerization" hypothesis that tumors arise within a transformed field with an altered biochemical phenotype, we sought to test if metabolic profiling could differentiate between histologically normal tissue from individuals with and without esophageal cancer. Thirty-five patients with esophageal adenocarcinoma and 52 age-matched controls participated in the study. Using 1H magic angle spinning-nuclear magnetic resonance spectroscopy of intact tissue, we generated metabolic profiles of tumor tissue, proximal histologically normal mucosa from cancer patients (PHINOM), and proximal histologically normal mucosa from a control group. Using multivariate regression and receiver-operator characteristic analysis, we identified a panel of metabolites discriminating malignant and histologically normal tissues from cancer patients and from that of controls. Whereas 26% and 12% of the spectral profile regions were uniquely discriminating tumor or control tissue, respectively, 5% of the profile exhibited a significant progressive change in signal intensity from controls to PHINOM to tumor. Regions identified were assigned to phosphocholine (PC), glutamate (Glu), myo-inositol, adenosine-containing compounds, uridine-containing compounds, and inosine. In particular, the PC/Glu ratio in histologically normal tissue signified the presence of esophageal cancer (n=123; area under the curve, 0.84; P<0.001). In conclusion, our findings support the hypothesis of the presence of metabonomic field effects in esophageal cancer, even in non-Barrett's segments. This indicates that metabolic profiling of tissue can potentially play a role in the surveillance of cancer by reporting on the phenotypic consequences of field cancerization.

Department of Surgery and Cancer, Imperial College London, St. Mary's Hospital, London

Cardwell CR, Abnet CC, Cantwell MM, Murray LJ
Exposure to oral bisphosphonates and risk of esophageal cancer.
JAMA. 2010; 304(6):657-63 [PubMed] Article available free on PMC after 15/09/2013

CONTEXT: Use of oral bisphosphonates has increased dramatically in the United States and elsewhere. Esophagitis is a known adverse effect of bisphosphonate use, and recent reports suggest a link between bisphosphonate use and esophageal cancer, but this has not been robustly investigated.
OBJECTIVE: To investigate the association between bisphosphonate use and esophageal cancer.
DESIGN, SETTING, AND PARTICIPANTS: Data were extracted from the UK General Practice Research Database to compare the incidence of esophageal and gastric cancer in a cohort of patients treated with oral bisphosphonates between January 1996 and December 2006 with incidence in a control cohort. Cancers were identified from relevant Read/Oxford Medical Information System codes in the patient's clinical files. Cox proportional hazards modeling was used to calculate hazard ratios and 95% confidence intervals for risk of esophageal and gastric cancer in bisphosphonate users compared with nonusers, with adjustment for potential confounders.
MAIN OUTCOME MEASURE: Hazard ratio for the risk of esophageal and gastric cancer in the bisphosphonate users compared with the bisphosphonate nonusers.
RESULTS: Mean follow-up time was 4.5 and 4.4 years in the bisphosphonate and control cohorts, respectively. Excluding patients with less than 6 months' follow-up, there were 41 826 members in each cohort (81% women; mean age, 70.0 (SD, 11.4) years). One hundred sixteen esophageal or gastric cancers (79 esophageal) occurred in the bisphosphonate cohort and 115 (72 esophageal) in the control cohort. The incidence of esophageal and gastric cancer combined was 0.7 per 1000 person-years of risk in both the bisphosphonate and control cohorts; the incidence of esophageal cancer alone in the bisphosphonate and control cohorts was 0.48 and 0.44 per 1000 person-years of risk, respectively. There was no difference in risk of esophageal and gastric cancer combined between the cohorts for any bisphosphonate use (adjusted hazard ratio, 0.96 [95% confidence interval, 0.74-1.25]) or risk of esophageal cancer only (adjusted hazard ratio, 1.07 [95% confidence interval, 0.77-1.49]). There also was no difference in risk of esophageal or gastric cancer by duration of bisphosphonate intake.
CONCLUSION: Among patients in the UK General Practice Research Database, the use of oral bisphosphonates was not significantly associated with incident esophageal or gastric cancer.

Centre for Public Health, Queen's University Belfast, Grosvenor Rd, Belfast BT12 6BJ

Lazzarino AI, Nagpal K, Bottle A, et al.
Open versus minimally invasive esophagectomy: trends of utilization and associated outcomes in England.
Ann Surg. 2010; 252(2):292-8 [PubMed]

OBJECTIVE: To assess the trends in uptake of minimal invasive esophagectomy in England over the last 12 years (1996/1997-2007/2008) and to compare their clinical outcomes with those after open esophagectomy.
SUMMARY OF BACKGROUND DATA: Around 7400 people are affected each year in the United Kingdom. Prognosis following esophageal resection is, however, poor. Even after "curative" surgery, 5-year survival rates do not exceed 25%. The minimally invasive approach to esophagectomy has attracted attention as a potentially less invasive alternative to conventional surgery.
METHODS: Data on patients undergoing esophagectomy for esophageal cancer were extracted from a national administrative database. The outcomes of interest were in-hospital mortality, 30-day in-hospital mortality, 30-day total (ie, in and out of hospital) mortality, 365-day total mortality, 28-day emergency readmission rates, and length of hospital stay. Hierarchical logistic regression was used to identify the effect of minimal invasive esophagectomy (MIE) on the outcomes after adjustment for age, gender, socioeconomic deprivation, and comorbidity.
RESULTS: A total of 18,673 esophagectomies were performed over the 12-year study period. The use of minimal access surgery increased exponentially over time (from 0.6% in 1996/1997 to 16.0% in 2007/2008). There was a suggestion that patients undergoing MIE had better 1-year survival rates than patients receiving open esophagectomy (OR = 0.68, 95% CI = 0.46-1.01, P = 0.058).
CONCLUSION: The uptake of MIE in England is increasing exponentially. With the possible exception of 1-year survival, patients selected for MIE demonstrated similar mortality and length of stay outcomes when compared with those undergoing conventional surgery. These results need to be confirmed in large-scale randomized controlled trials.

Dr Foster Unit at Imperial College, Department of Primary Care and Social Medicine, Imperial College London, London