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Background Surveillance of premalignant gastric lesions relies mainly on random biopsy sampling. Narrow band imaging (NBI) may enhance the accuracy of endoscopic surveillance of intestinal metaplasia (IM) and dysplasia. We aimed to compare the yield of NBI to white light endoscopy (WLE) in the surveillance of patients with IM and dysplasia. Methods Patients with previously identified gastric IM or dysplasia underwent a surveillance endoscopy. Both WLE and NBI were performed in all patients during a single procedure. The sensitivity of WLE and NBI for the detection of premalignant lesions was calculated by correlating endoscopic findings to histological diagnosis. Results Forty-three patients (28 males and 15 females, mean age 59 years) were included. IM was diagnosed in 27 patients; 20 were detected by NBI and WLE, four solely by NBI and three by random biopsies only. Dysplasia was detected in seven patients by WLE and NBI and in two patients by random biopsies only. Sixty-eight endoscopically detected lesions contained IM: 47 were detected by WLE and NBI, 21 by NBI only. Nine endoscopically detected lesions demonstrated dysplasia: eight were detected by WLE and NBI, one was detected by NBI only. The sensitivity, specificity, positive and negative predictive values for detection of premalignant lesions were 71, 58, 65 and 65% for NBI and 51, 67, 62 and 55% for WLE, respectively. Conclusions NBI increases the diagnostic yield for detection of advanced premalignant gastric lesions compared to routine WLE.

We have constructed a high-resolution genomic microarray of human chromosome 16q, and used it for comparative genomic hybridization analysis of 16 prostate tumors. We demarcated 10 regions of genomic loss between 16q23.1 and 16qter that occurred in five or more samples. Mining expression array data from four independent studies allowed us to identify 11 genes that were frequently underexpressed in prostate cancer and that co-localized with a region of genomic loss. Quantitative expression analyses of these genes in matched tumor and benign tissue from 13 patients showed that six of these 11 (WWOX, WFDC1, MAF, FOXF1, MVD and the predicted novel transcript Q9H0B8 (NM_031476)) had significant and consistent downregulation in the tumors relative to normal prostate tissue expression making them candidate tumor suppressor genes.

Adenocarcinoma of the esophagus, or GEJ, has a poor prognosis. Early lesions [i.e. high grade dysplasia (HGD) or T1-carcinoma] are potentially curable. Local endoscopic therapies are promising treatment options for superficial lesions; however, for deeper lesions, surgical resection is considered to be the treatment of choice. To contribute to therapeutic decision-making, we retrospectively analysed the outcome of transhiatal esophagectomy in 120 patients with pathologically proven HGD (n=13) or T1-adenocarcinoma (n=107) of the distal esophagus or gastro-esophageal junction (GEJ). Tumors were subdivided into six different depths of invasion ('T1-mucosal' m1-m3, 'T1-submucosal' sm1-sm3), and the frequency of lymphatic dissemination and time to locoregional and/or distant recurrence were analysed. Only one of the 79 T1m1-3/sm1 tumors (1%) showed lymph node metastases as compared with 18 out of 41 T1sm2-3 tumors (44%). There was a significant difference in recurrence-free period between T1m1-m3/sm1 versus T1sm2-sm3 tumor patients (P log rank <0.0001), with 5-year recurrence-free percentages of 97% and 57%, respectively. In multivariate analysis including age, gender, tumor differentiation grade, N-stage and depth of invasion, only N-stage was an independent prognostic factor for recurrence-free period (hazard rate=5.9, 95% CI 1.7-20.7). However, if N-stage was excluded from analysis, only depth of invasion (T1sm2-3 versus T1m1-m3/sm1) was an independent prognostic factor for recurrence-free period (hazard rate=7.5, 95% CI 2.0-27.7). These data indicate that T1m1-m3/sm1 adenocarcinomas of esophagus or GEJ show a very low risk of lymphatic dissemination and are therefore eligible for local endoscopic therapy. After transhiatal surgical resection, almost half of the patients with T1sm2-sm3 lesions develop recurrent disease within 5 years, and therefore need additional therapy to improve survival.

Surveillance of patients with Barrett's esophagus (BE) aims at early detection and treatment of neoplastic changes, particularly esophageal adenocarcinoma (EAC). The histological evaluation of biopsy samples has its limitations, and biomarkers may improve early identification of BE patients at risk for progression to EAC. The aim of this study was to determine the predictive value of p53, Ki67, and aneuploidy as markers of neoplastic progression in BE. A total of 27 BE patients with histologically proven progression to high-grade dysplasia (HGD) or EAC (cases) and 27 BE patients without progression (controls) were selected and matched for age, gender, and duration of follow-up. Dysplasia grade was determined in 212 biopsy samples obtained during surveillance endoscopies from cases and in 231 biopsy samples collected from controls. DNA ploidy status was determined by flow cytometry, whereas Ki67 and p53 expression was determined by immunohistochemistry. Hazard ratios (HRs) were calculated by Cox regression adjusted for potentially confounding variables. A univariate analysis showed that low-grade dysplasia (LGD) increased the risk of developing HGD/EAC compared with no dysplasia (HR 3.6; 95% confidence interval (CI): 1.6 - 8.1). Aneuploidy (HR 3.5; 95% CI: 1.3-9.4), strong Ki67 overexpression (HR 5.2; 95% CI: 1.5-17.6), and moderate p53 overexpression (HR 6.5; 95% CI: 2.5-17.1) were also associated with an increased risk of developing HGD/EAC, independent of the histological result. A multivariable analysis showed that in the presence of LGD, p53 overexpression, and to a lesser extent, Ki67 overexpression remained important risk factors for neoplastic progression, whereas aneuploidy was no longer predictive. p53 overexpression and, to a lesser extent, Ki67 overexpression could predict neoplastic progression in BE irrespective of the histological result. These markers may be useful for identifying patients at an increased risk of developing EAC, either alone or used as a panel.

BackgroundTacrolimus is a potent immunomodulator that is effective in the systemic treatment of inflammatory bowel diseases (IBD). However, potential toxicity and systemic (side) effects after oral intake limit its use. We investigated the local applicability and safety of tacrolimus for distal colitis.MethodsPatients with refractory left-sided colitis or proctitis were treated for 4 weeks with a daily tacrolimus 2–4 mg enema or 2 mg suppository. Safety of local tacrolimus treatment was assessed by measurement of whole blood tacrolimus trough levels by monitoring liver and kidney function and blood glucose levels. Efficacy of treatment was assessed by comparing the disease activity index (DAI) in ulcerative colitis (UC) patients and endoscopic and histologic appearances before and after 4 weeks of treatment.ResultsNineteen patients with left-sided colitis (n = 7) or proctitis (n = 12) were treated. Two patients with left-sided colitis had Crohn's disease (CD), the other 17 patients had UC. None of the patients developed side effects. Blood trough levels of tacrolimus were too low to induce systemic immune suppression. Thirteen of 19 patients (3/5 left-sided UC, 0/2 left-sided CD, and 10/12 proctitis) showed clinical improvement of disease activity after 4 weeks of local tacrolimus treatment. Moreover, a significant improvement of histological appearance was observed in the suppository-treated group.ConclusionsThis study demonstrates that local colonic application of tacrolimus 2–4 mg daily in patients with refractory distal colitis is feasible, probably safe, and potentially efficacious, and therefore opens the need for a further, randomized trial.

Barrett's esophagus (BE) is a premalignant condition of the esophagus. It is a consequence of mucosal injury from chronic gastroesophageal reflux in which bile acids are an important toxic component. The farnesoid X receptor (FXR) is a nuclear receptor involved in the regulation of bile acid synthesis, transport, and absorption. FXR activation is also involved in the induction of the innate immune response. This suggests that FXR is involved in the pathogenesis and the inflammation seen in BE. mRNA levels of FXR and the FXR-regulated genes, ileal bile acid-binding protein (IBABP), small heterodimer partner (SHP), and chemokines interleukin (IL)-8 and macrophage inflammatory protein 3 alpha (MIP3 alpha), were determined by real time-polymerase chain reaction (RT-PCR). Protein expression was determined by immunohistochemistry. FXR was not expressed in squamous epithelium of healthy subjects (N = 7), but was present in both squamous and columnar epithelium of BE patients. Compared to the squamous epithelium of BE patients, their columnar epithelium displayed a 2.3-fold (P= 0.02) increase in FXR mRNA. Also, IBABP (2.2-fold; P= 0.0029), SHP (2.7-fold; P= 0.007), IL-8 (1.5-fold; P= 0.04), and MIP3 alpha (1.7-fold; P= 0.019) transcription levels were increased. Exposure of esophageal cell line TE7 to deoxycholic acid (DCA) resulted in a similar induction. The induction was abolished by the FXR antagonist guggulsterone. Expression levels of the bile acid receptor FXR, the bile acid metabolism genes IBABP and SHP, and the chemokines IL-8 and MIP3 alpha are increased in Barrett's epithelium. The in vitro induction of FXR by DCA suggests that bile acids can actively induce the inflammatory response in BE by recruiting immune cells.

Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years. Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2–3N0–1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m2 of body-surface area] for 23 days) with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed. Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84·1 months (range 61·1–116·8, IQR 70·7–96·6), median overall survival was 48·6 months (95% CI 32·1–65·1) in the neoadjuvant chemoradiotherapy plus surgery group and 24·0 months (14·2–33·7) in the surgery alone group (HR 0·68 [95% CI 0·53–0·88]; log-rank p=0·003). Median overall survival for patients with squamous cell carcinomas was 81·6 months (95% CI 47·2–116·0) in the neoadjuvant chemoradiotherapy plus surgery group and 21·1 months (15·4–26·7) in the surgery alone group (HR 0·48 [95% CI 0·28–0·83]; log-rank p=0·008); for patients with adenocarcinomas, it was 43·2 months (24·9–61·4) in the neoadjuvant chemoradiotherapy plus surgery group and 27·1 months (13·0–41·2) in the surgery alone group (HR 0·73 [95% CI 0·55–0·98]; log-rank p=0·038). Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer. Dutch Cancer Foundation (KWF Kankerbestrijding).

Reflux esophagitis (RO) and Barrett's esophagus (BO) can cause esophageal adenocarcinoma (OAC). The esophageal mucosa in the RO-BO-OAC cascade is chronically exposed to gastro-esophageal reflux. Epidermal growth factor (EGF) has an important role in the protection and repair of mucosal damage, and non-physiologic levels are associated with gastrointestinal tumors. The aim is to determine the functional effect of EGF gene polymorphisms on RO, BO and OAC development. A cohort of 871 unrelated Dutch Caucasians consisted of 198 healthy controls, 298 RO patients, 246 BO patients and 129 OAC patients. The frequency of the EGF-production-associated 5'UTR A+61G polymorphism was determined in these four groups. EGF immunohistochemistry was performed on BO biopsies. EGF expression was significantly lower in the G/G genotype compared with the A/G (P=0.008) and A/A (P=0.002) group. The G/G genotype was significantly more prevalent in RO (odds ratios (OR)=2.6; 95% confidence intervals (95% CI): 1.3-5.2), BO (OR=3.0; 95% CI: 1.5-6.2) and OAC (OR=4.1; 95% CI: 1.8-9.7) than in controls. The G allele is associated with reduced EGF expression and increased risk for RO, BO and OAC development. This indicates that reduced mucosal protection resulting from genetically decreased EGF expression enhances esophageal tumor development.

Despite the high incidence of prostate cancer, only limited data are available on genes or chromosomes specifically involved in its initiation and progression. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded, tissues at different times in prostatic tumor progression to screen the tumor genome for gains and losses. Our panel included specimens derived from 56 different patients: 23 patients with primary, prostate-confined carcinomas; 18 patients with regional lymph node metastases; and 15 patients with distant metastases. Chromosome arms that most frequently showed losses, included 13q (55%), 8p (48%), 6q (43%), 5q (32%), 16q (25%), 18q (20%), 2q (18%), 4q (18%), 10q (18%), and Y (16%). Gains were often seen of chromosome arms 8q (36%), 17q (23%), Xq (23%), 7q (21%), 3q (18%), 9q (18%), 1q (16%), Xp (16%). Furthermore, specific high-level amplifications, eg, of 1q21, 1q25, and Xq12 to q13, were found in metastatic cancers. A significant accumulation of genetic changes in distant metastases was observed, eg, loss of 10q (p = 0.03) and gain of 7q (p = 0.03) sequences. In addition, investigation of a potential biomarker identified in previous studies by our group, ie, extra copies of #7 and/or #8, revealed a high prevalence of 7pq and/or 8q gain in the distant metastases (p = 0.02). Importantly, gains were observed more frequently in tumors derived from progressors after radical prostatectomy, than in nonprogressors (mean time of follow-up, 74 months). Specifically, gain of chromosome 7pq and/or 8q sequences appeared an accurate discriminator between the progressors and nonprogressors. Multivariate analysis showed a significant correlation between progressive disease and the number of chromosomes with gains. This correlation also held true when stage (p = 0.007) or grade (p = 0.002) were taken into account. Likewise, this applied for gain of chromosome 7pq and/or 8q sequences (p = 0.03 and p = 0.005 for stage or grade, respectively). Additionally, an increase in the number of chromosomes with gains per case was related to a decrease in biochemical progression-free survival (Ptrend <0.001). More specifically, the gain of 7pq and/or 8q sequences markedly reduced the biochemical progression-free survival (p < 0.001). In conclusion, this study has, firstly, documented the spectrum of chromosomal alterations in subsequent stages of prostate cancer, a number of which had not been described previously. It allowed us to identify chromosomal regions related to advanced tumor stage, ie, loss of 10q24 and gain of 7q11.2 and/or 7q31 sequences. Secondly, gain of 7pq and/or 8q was identified as a potential genetic discriminator between progressors and nonprogressors after radical surgery.

Background The continuous exposure of esophageal epithelium to refluxate may induce ectopic expression of bile-responsive genes and contribute to the development of Barrett's esophagus (BE) and esophageal adenocarcinoma. In normal physiology of the gut and liver, the nuclear receptor Pregnane × Receptor (PXR) is an important factor in the detoxification of xenobiotics and bile acid homeostasis. This study aimed to investigate the expression and genetic variation of PXR in reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma. Methods PXR mRNA levels and protein expression were determined in biopsies from patients with adenocarcinoma, BE, or RE, and healthy controls. Esophageal cell lines were stimulated with lithocholic acid and rifampicin. PXR polymorphisms 25385C/T, 7635A/G, and 8055C/T were genotyped in 249 BE patients, 233 RE patients, and 201 controls matched for age and gender. Results PXR mRNA levels were significantly higher in adenocarcinoma tissue and columnar Barrett's epithelium, compared to squamous epithelium of these BE patients ( P < 0.001), and RE patients ( P = 0.003). Immunohistochemical staining of PXR showed predominantly cytoplasmic expression in BE tissue, whereas nuclear expression was found in adenocarcinoma tissue. In cell lines, stimulation with lithocholic acid did not increase PXR mRNA levels, but did induce nuclear translocation of PXR protein. Genotyping of the PXR 7635A/G polymorphism revealed that the G allele was significantly more prevalent in BE than in RE or controls ( P = 0.037). Conclusions PXR expresses in BE and adenocarcinoma tissue, and showed nuclear localization in adenocarcinoma tissue. Upon stimulation with lithocholic acid, PXR translocates to the nuclei of OE19 adenocarcinoma cells. Together with the observed association of a PXR polymorphism and BE, this data implies that PXR may have a function in prediction and treatment of esophageal disease.