Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial.

BACKGROUND: 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. METHODS: 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/m(2) 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Dutch Cancer Foundation (KWF Kankerbestrijding).

Lymph Node Yield in Colon Cancer: Individuals Can Make the Difference.

AIM: To investigate the influence of individual surgeons and pathologists on examining an adequate (i.e. ≥10) number of lymph nodes in colon cancer resection specimens. PATIENTS AND METHODS: The number of lymph nodes was evaluated in surgically treated patients for colon cancer at our hospital from 2008 through 2010, excluding patients who had received neo-adjuvant treatment. The patient group consisted of 156 patients with a median age of 73 (interquartile range (IQR) 63-82 years) and a median of 12 lymph nodes per patient (IQR 8-15). In 106 patients (67.9%), 10 or more nodes were histopathologically examined. RESULTS: At univariate analysis, the examination of ≥10 nodes was influenced by tumour size (p = 0.05), tumour location (p = 0.015), type of resection (p = 0.034), individual surgeon (p = 0.023), and pathologist (p = 0.005). Neither individual surgeons nor pathologists did statistically and significantly influence the chance of finding an N+ status. Age (p = 0.044), type of resection (p = 0.007), individual surgeon (p = 0.012) and pathologist (p = 0.004) were independent prognostic factors in a multivariate model for finding ≥10 nodes. CONCLUSION: Though cancer staging was not affected in this study, individual efforts by surgeons and pathologists play a critical role in achieving optimal lymph node yield through conventional methods.

Long-term survival after resection for non-pancreatic periampullary cancer followed by adjuvant intra-arterial chemotherapy and concomitant radiotherapy.

BACKGROUND: There is no consensus regarding the optimal adjuvant treatment after resection of non-pancreatic periampullary adenocarcinoma (NPPC; distal common bile duct, ampulla, duodenum). OBJECTIVES: The present study was conducted to evaluate the impacts on longterm survival and recurrence of adjuvant intra-arterial chemotherapy (IAC) and concomitant radiotherapy (RT) in patients submitted to resection for NPPC or pancreatic ductal adenocarcinoma (PDAC) in a randomized controlled trial. METHODS: A total of 120 patients with PDAC (n = 62) or NPPC (n = 58) were prestratified at a ratio of 1:1 for tumour origin and randomized. Half of these patients were treated with adjuvant IAC/RT and the other half were treated with surgery alone. Follow-up was completed for all patients up to 5 years after resection or until death. RESULTS: There was no survival benefit in either the whole group (primary endpoint) or the PDAC group after IAC/RT. In the NPPC group, longterm survival was observed in 10 patients in the IAC/RT group and five patients in the control group: median survival was 37 months and 28 months, respectively. The occurrence of liver metastases was reduced by IAC/RT from 57% to 29% (P = 0.038). Cox regression analysis revealed a substantial effect of IAC/RT on survival (hazard ratio: 0.44, 95% confidence interval 0.23-0.83; P = 0.011). CONCLUSIONS: This longterm analysis shows that median and longterm survival were improved after IAC/RT in patients with NPPC, probably because of the effective and sustained reduction of liver metastases. The present results illustrate that NPPC requires an adjuvant approach distinct from that in pancreatic cancer and indicate that further investigation of this issue is warranted.

Lymph node retrieval during esophagectomy with and without neoadjuvant chemoradiotherapy: prognostic and therapeutic impact on survival.

OBJECTIVES: We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT. BACKGROUND: Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently "sterilize" regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful. METHODS: Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups. RESULTS: One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12-27) and 14 (9-21), with 2 (1-6) and 0 (0-1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P=0.007), but not in the multimodality arm (hazard ratio 1.00; P=0.98). CONCLUSIONS: The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

Functional single-nucleotide polymorphism of epidermal growth factor is associated with the development of Barrett's esophagus and esophageal adenocarcinoma.

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.

Cyst-like schwannoma on the eyelid margin.

Schwannomas are benign tumors originating from Schwann cells. We describe a rare case of solitary schwannoma on the eyelid margin. To our knowledge, this is the first clinical report of such a lesion on the eyelid margin, confirmed by both extensive immunohistochemical analysis and its distinctive morphology. Although schwannomas seldom undergo malignant change, they should be considered in the differential diagnosis of palpebral lesions.

Fluorodeoxyglucose positron emission tomography for evaluating early response during neoadjuvant chemoradiotherapy in patients with potentially curable esophageal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy before surgery can improve survival in patients with potentially curable esophageal cancer, but not all patients respond. Fluorodeoxyglucose positron emission tomography (FDG-PET) has been proposed to identify nonresponders early during neoadjuvant chemoradiotherapy. The aim of the present study was to determine whether FDG-PET could differentiate between responding and nonresponding esophageal tumors early in the course of neoadjuvant chemoradiotherapy. METHODS: This clinical trial comprised serial FDG-PET before and 14 days after start of chemoradiotherapy in patients with potentially curable esophageal carcinoma. Histopathologic responders were defined as patients with no or less than 10% viable tumor cells (Mandard score on resection specimen). PET response was measured using the standardized uptake value (SUV). Receiver operating characteristic analysis was used to evaluate the ability of SUV in distinguishing between histopathologic responders and nonresponders. RESULTS: In 100 included patients, 64 were histopathologic responders. The median SUV decrease 14 days after the start of therapy was 30.9% for histopathologic responders and 1.7% for nonresponders (P = 0.001). In receiver operating characteristic analysis, the area under the curve was 0.71 (95% CI = 0.60-0.82). Using a 0% SUV decrease cutoff value, PET correctly identified 58 of 64 responders (sensitivity 91%) and 18 of 36 nonresponders (specificity 50%). The corresponding positive and negative predictive values were 76% and 75%, respectively. CONCLUSIONS: SUV decrease 14 days after the start of chemoradiotherapy was significantly associated with histopathologic tumor response, but its accuracy in detecting nonresponders was too low to justify the clinical use of FDG-PET for early discontinuation of neoadjuvant chemoradiotherapy in patients with potentially curable esophageal cancer.

Differential expression of the nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) for grading dysplasia in patients with Barrett's oesophagus.

AIMS: To investigate expression of nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) as a diagnostic tool to improve grading of dysplasia in Barrett's oesophagus patients. METHODS AND RESULTS: Immunostaining was analysed on a total of 192 biopsy samples of 22 Barrett's patients with no dysplasia (ND), 17 with low-grade dysplasia (LGD), 20 high-grade dysplasia (HGD) and 24 with adenocarcinoma (AC). Nuclear FXR expression was observed in 15 of 22 (68%) ND cases versus none of 19 HGD; 3 of 17 (18%); LGD; 5 of 60 (8%) patients with AC (P<0.001). FXR expression was highly specific for non-dysplastic tissue. Nuclear PXR was expressed in 16 of 20 (80%) HGD cases versus two of 16 (13%) LGD cases (PPV 89%). Upon examining adjacent tissue taken from HGD and AC patients, PXR expression was high in samples of all tissue types. CONCLUSIONS: Nuclear receptors are expressed differentially during neoplastic progression, with FXR positivity being useful to distinguish ND from dysplasia and AC. PXR nuclear expression is able to separate HGD from LGD and ND. The combination of FXR and PXR also appears to have diagnostic and possibly prognostic value, but future prospective studies are required to investigate their predictive power for neoplastic progression in Barret's oesophagus.

Inter-observer variation in the histological diagnosis of polyps in colorectal cancer screening.

AIM: To determine the inter-observer variation in the histological diagnosis of colorectal polyps. METHODS AND RESULTS: Four hundred and forty polyps were randomly selected from a colorectal cancer screening programme. Polyps were first evaluated by a general (324 polyps) or expert (116 polyps) pathologist, and subsequently re-evaluated by an expert pathologist. Conditional agreement was reported, and inter-observer agreement was determined using kappa statistics. In 421/440 polyps (96%), agreement for their non-adenomatous or adenomatous nature was obtained, corresponding to a very good kappa value of 0.88. For differentiation of adenomas as non-advanced and advanced, consensus was obtained in 266/322 adenomas (83%), with a moderate kappa value of 0.58. For the non-adenomatous or adenomatous nature, both general and expert pathologists, and expert pathologists between each other, showed very good agreement {kappa values of 0.89 [95% confidence interval (CI) 0.83-0.95] and 0.86 (95% CI 0.73-0.98), respectively}. For categorization of adenomas as non-advanced and advanced, moderate agreement was found between general and expert pathologists, and between expert pathologists [kappa values of 0.56 (95% CI 0.44-0.67) and 0.64 (95% CI 0.43-0.85), respectively]. CONCLUSIONS: General and expert pathologists demonstrate very good inter-observer agreement for differentiating non-adenomas from adenomas, but only moderate agreement for non-advanced and advanced adenomas. The considerable variation in differentiating non-advanced and advanced adenomas suggests that more objective criteria are required for risk stratification in screening and surveillance guidelines.

Expression, localization and polymorphisms of the nuclear receptor PXR in Barrett's esophagus and esophageal adenocarcinoma.

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.

Barrett's oesophageal adenocarcinoma encompasses tumour-initiating cells that do not express common cancer stem cell markers.

Accumulating evidence has suggested that tumours have a hierarchical organization in which only the cancer stem cells (CSCs) have tumour-initiating properties. Several surface antigens have been employed to isolate CSCs from various malignancies, although not from oesophageal adenocarcinoma (EA). We tested whether Barrett's oesophagus (BE) and EA might serve as a model for the CSC concept. In vivo assays were performed by transplantation of serially diluted bulk EA cells into NOD-SCID mice to establish the presence and frequency of tumour-initiating cells. These were found to be present as ca. 1 in 64 000 cells. The transplanted tumours fully recapitulated the primary lesions. Subsequently, a panel of previously established CSC markers was employed for immunohistochemistry. CD24, CD29 and CD44 showed heterogeneous staining in EA. Nuclear beta-catenin accumulation increased during progression from metaplasia to dysplasia and was often observed in the basal compartment with CD24 and CD29 staining. However, the overall staining patterns were not such to clearly point out specific candidate markers. Accordingly, all markers were employed to sort the corresponding subpopulations of cancer cells and transplant them at low multiplicities in NOD-SCID mice. No increased tumour-initiating capacity of sorted EA cells was observed upon transplantation. These results indicate that tumour-initiating cells are present in EA, thus reflecting a hierarchical organization. However, antibodies directed against novel surface antigens are needed to detect subpopulations enriched for CSCs in EA by transplantation assays.

A back-to-back comparison of white light video endoscopy with autofluorescence endoscopy for adenoma detection in high-risk subjects.

OBJECTIVE: To compare the sensitivity of autofluorescence endoscopy (AFE) and white light video endoscopy (WLE) for the detection of colorectal adenomas in high-risk patients belonging to Lynch syndrome (LS) or familial colorectal cancer (CRC) families. METHODS: This was a prospective single-centre study carried out in a tertiary referral centre. The subjects were 75 asymptomatic patients originating from LS or familial CRC families. Patients were examined with either WLE followed by AFE or AFE followed by WLE. Back-to-back colonoscopy was performed by two blinded endoscopists. All lesions were removed during the second endoscopic procedure. Lesions missed during the second procedure were identified and removed on third pass. The sensitivity calculations for colorectal adenomas were based on histology results. The main outcome measures were the difference in sensitivity between WLE and AFE for the detection of adenomas in patients with LS or familial CRC. RESULTS: At least one adenoma was detected in 41 (55%) patients. WLE identified adenomas in 28/41 patients and AFE in 37/41 patients, corresponding to a 32% increase. In total 95 adenomas were detected, 65 by WLE and 87 by AFE, resulting in a significantly higher sensitivity of AFE compared with WLE (92% vs 68%; p=0.001). The additionally detected adenomas with AFE were significantly smaller than the adenomas detected by WLE (mean 3.0 mm vs 4.9 mm, p<0.01). CONCLUSIONS: AFE improves the detection of colorectal adenomas in patients with LS or familial CRC. The results of this study suggest that AFE may be preferable for surveillance of these high-risk patients.

The staging of gastritis with the OLGA system by using intestinal metaplasia as an accurate alternative for atrophic gastritis.

BACKGROUND: The OLGA (operative link on gastritis assessment) staging system is based on severity of atrophic gastritis (AG). AG remains a difficult histopathologic diagnosis with low interobserver agreement, whereas intestinal metaplasia (IM) is associated with high interobserver agreement. OBJECTIVE: The aim of this study was to evaluate whether a staging system based on IM is preferable to estimate gastric cancer risk. DESIGN AND SETTING: Prospective multicenter study. PATIENTS: A total of 125 patients previously diagnosed with gastric IM or dysplasia. INTERVENTIONS: Surveillance endoscopy with extensive biopsy sampling. MAIN OUTCOME MEASUREMENTS: Three pathologists graded biopsy specimens according to the Sydney classification. Interobserver agreement was analyzed by kappa statistics. In the OLGA, AG was replaced by IM, creating the OLGIM. RESULTS: Interobserver agreement was fair for dysplasia (kappa = 0.4), substantial for AG (kappa = 0.6), almost perfect for IM (kappa = 0.9), and improved for all stages of OLGIM compared with OLGA. Overall, 84 (67%) and 79 (63%) patients were classified as stage I-IV according to OLGA and OLGIM, respectively. Of the dysplasia patients, 5 (71%) and 6 (86%) clustered in stage III-IV of OLGA and OLGIM, respectively. LIMITATION: Prospective studies should confirm the correlation between gastric cancer risk and OLGIM stages. CONCLUSION: Replacement of AG by IM in the staging of gastritis considerably increases interobserver agreement. The correlation with the severity of gastritis remains at least as strong. Therefore, the OLGIM may be preferred over the OLGA for the prediction of gastric cancer risk in patients with premalignant lesions.

Biopsy strategies for endoscopic surveillance of pre-malignant gastric lesions.

BACKGROUND: Endoscopic surveillance of pre-malignant gastric lesions may add to gastric cancer prevention. However, the appropriate biopsy regimen for optimal detection of the most advanced lesions remains to be determined. Therefore, we evaluated the yield of endoscopic surveillance by standardized and targeted biopsy protocols. MATERIALS AND METHODS: In a prospective, multi-center study, patients with intestinal metaplasia (IM) or dysplasia (DYS) underwent a surveillance gastroscopy. Both targeted biopsies from macroscopic lesions and 12 non-targeted biopsies according to a standardized protocol (antrum, angulus, corpus, cardia) were obtained. Appropriate biopsy locations and the yield of targeted versus non-targeted biopsies were evaluated. RESULTS: In total, 112 patients with IM (n = 101), or low-grade (n = 5) and high-grade DYS (n = 6) were included. Diagnosis at surveillance endoscopy was atrophic gastritis (AG) in one, IM in 77, low-grade DYS in two, high-grade DYS in three, and gastric cancer in one patient. The angulus (40%), antrum (35%) and lesser curvature of the corpus (33%) showed the highest prevalence of pre-malignant conditions. Non-targeted biopsies from the lesser curvature had a significantly higher yield as compared to the greater curvature of the corpus in diagnosing AG and IM (p = .05 and p = .03). Patients with extensive intragastric IM, which was also present at the cardia were at high risk of a concurrent diagnosis of dysplasia or gastric cancer. High-grade DYS was detected in targeted biopsies only. CONCLUSIONS: At surveillance endoscopies, both targeted and non-targeted biopsies are required for an appropriate diagnosis of (pre-)malignant gastric lesions. Non-targeted biopsies should be obtained in particular from the antrum, angulus and lesser curvature of the corpus.

Narrow band imaging for the detection of gastric intestinal metaplasia and dysplasia during surveillance endoscopy.

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 (IMa)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.

Aneuploidy and overexpression of Ki67 and p53 as markers for neoplastic progression in Barrett's esophagus: a case-control study.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The use of clinical, histologic, and serologic parameters to predict the intragastric extent of intestinal metaplasia: a recommendation for routine practice.

BACKGROUND: Surveillance of intestinal metaplasia (IM) of the gastric mucosa should be limited to patients at high risk of gastric cancer. Patients with extensive IM are at increased cancer risk; however, the intragastric extent of IM is usually unknown at the time of the initial diagnosis. OBJECTIVE: To assess the predictive value of clinical, histologic, and serologic parameters for the intragastric extent of IM. DESIGN AND SETTING: Prospective, multicenter study. PATIENTS: Eighty-eight patients with a previous diagnosis of IM of the gastric mucosa. INTERVENTION: Surveillance gastroscopy with extensive random biopsy sampling. MAIN OUTCOME MEASUREMENTS: Biopsy specimens were evaluated according to the Sydney classification system. In addition, serologic testing of Helicobacter pylori and cagA status, pepsinogens I and II, gastrin, and intrinsic factor antibodies was performed. The association between the available parameters and extensive IM was evaluated with logistic regression analysis. RESULTS: In 51 patients (58%), IM was present in the biopsy specimens from at least 2 intragastric locations. The most important predictors of extensive IM were a family history of gastric cancer, alcohol use > or = 1 unit/d (1 glass, approximately 10 mL or 8 g ethanol), moderate or marked IM of the index biopsy specimen, and a pepsinogen I to II ratio < 3.0. A simple risk score based on these factors could identify extensive IM in 24 of 25 patients (sensitivity 96%). LIMITATION: A prospective cohort study should confirm the proposed risk stratification. CONCLUSIONS: A risk score of clinical, histologic, and serologic parameters can predict extensive intragastric IM and may serve as a practical tool to select patients for surveillance endoscopy in routine clinical practice.

Serum levels of leptin as marker for patients at high risk of gastric cancer.

BACKGROUND: Serological screening for gastric cancer (GC) may reduce mortality. However, optimal serum markers for advanced gastric precursor lesions are lacking. AIM: To evaluate in a case-control study whether serum leptin levels correlate with intestinal metaplasia (IM) and can serve as a tool to identify patients at high risk for GC. MATERIALS AND METHODS: Cases were patients with a previous diagnosis of IM or dysplasia, controls were patients without such a diagnosis. All patients underwent endoscopy. Fasting serum was collected for the measurement of leptin, pepsinogens I/II, gastrin, and Helicobacter pylori. Receiver operating characteristic (ROC) curves and their area under the curve (AUC) were provided to compare serum leptin levels with other serological markers. RESULTS: One hundred nineteen cases and 98 controls were included. In cases, the median leptin levels were 116.6 pg/mL versus 81.9 pg/mL in controls (p = .01). After adjustment for age, sex and BMI, leptin levels remained higher in cases than in controls (p < .005). In multivariate analysis, male sex (p = .002), age (<0.001), low pepsinogen levels (p = .004) and high leptin levels (p = .04) were independent markers for the presence of IM. In addition, a ROC curve including age, sex and pepsinogen I levels had an AUC of 0.79 (95% CI (0.73-0.85)). Adding serum leptin levels increased the AUC to 0.81 (95% CI (0.75-0.86)). CONCLUSIONS: High leptin levels are associated with an increased risk of IM. Moreover, serum leptin levels are a significant independent marker for the presence of IM. However, in combination with the serological test for pepsinogen I the additional value of serum leptin levels is rather limited.

Mistaken identity of widely used esophageal adenocarcinoma cell line TE-7.

Cancer of the esophagus is the seventh leading cause of cancer death worldwide. Esophageal carcinoma cell lines are useful models to study the biological and genetic alterations in these tumors. An important prerequisite of cell line research is the authenticity of the used cell lines because the mistaken identity of a cell line may lead to invalid conclusions. Estimates indicate that up to 36% of the cell lines are of a different origin or species than supposed. The TE series, established in late 1970s and early 1980s by Nishihira et al. in Japan, is one of the first esophageal cancer cell line series that was used throughout the world. Fourteen TE cell lines were derived from human esophageal squamous cell carcinomas and one, TE-7, was derived from a primary esophageal adenocarcinoma. In numerous studies, this TE-7 cell line was used as a model for esophageal adenocarcinoma because it is one of the few esophageal adenocarcinoma cell lines existing. We investigated the authenticity of the esophageal adenocarcinoma cell line TE-7 by xenografting, short tandem repeat profiling, mutation analyses, and array-comparative genomic hybridization and showed that cell line TE-7 shared the same genotype as the esophageal squamous cell carcinoma cell lines TE-2, TE-3, TE-12, and TE-13. In addition, for more than a decade, independent TE-7 cultures from Japan, United States, United Kingdom, France, and the Netherlands had the same genotype. Examination of the TE-7 cell line xenograft revealed the histology of a squamous cell carcinoma. We conclude that the TE-7 cell line, used in several laboratories throughout the world, is not an adenocarcinoma, but a squamous cell carcinoma cell line. Furthermore, the cell lines TE-2, TE-3, TE-7, TE-12, and TE-13 should be regarded as one single squamous cell carcinoma cell line.

Adjuvant intra-arterial chemotherapy and radiotherapy versus surgery alone in resectable pancreatic and periampullary cancer: a prospective randomized controlled trial.

BACKGROUND: Success of surgical treatment for pancreatic and periampullary cancer is often limited due to locoregional recurrence and/or the development of distant metastases. OBJECTIVE: The survival benefit of celiac axis infusion (CAI) and radiotherapy (RT) versus observation after resection of pancreatic or periampullary cancer was investigated. METHODS: In a randomized controlled trial, 120 consecutive patients with histopathologically proven pancreatic or periampullary cancer received either adjuvant treatment consisting of intra-arterial mitoxantrone, 5-FU, leucovorin, and cisplatinum in combination with 30 x 1.8 Gy radiotherapy (group A) or no adjuvant treatment (group B). Groups were stratified for tumor type (pancreatic vs. periampullary tumors). RESULTS: After surgery, 120 patients were randomized (59 patients in the treatment group, 61 in the observation group). The median follow-up was 17 months. No significant overall survival benefit was seen (median, 19 vs. 18 months resp.). Progressive disease was seen in 86 patients: in 37 patients in the CAI/RT group, and in 49 patients in the observation group (log-rank P < 0.02). Subgroup analysis showed significantly less liver metastases after adjuvant treatment in periampullary tumors (log-rank P < 0.03) without effect on local recurrence. Nonetheless, there was no significant effect on overall survival in these patients (log-rank P = 0.15). In patients with pancreatic cancer, CAI/RT had no significant effect on local recurrence (log-rank P = 0.12) neither on the development of liver metastases (log-rank P = 0.76) and consequently, no effect on overall survival. CONCLUSION: This adjuvant treatment schedule results in a prolonged time to progression. For periampullary tumors, CAI/RT induced a significant reduction in the development of liver metastases, with a possible effect on overall survival. Especially in these tumors, CAI/RT might prove beneficial in larger groups and further research is warranted.