Individual risk calculator to predict lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma: a multicenter cohort study.

BACKGROUND: Lymph node metastasis (LNM) is possible after endoscopic resection of early esophageal adenocarcinoma (EAC). This study aimed to develop and internally validate a prediction model that estimates the individual risk of metastases in patients with pT1b EAC. METHODS: A nationwide, retrospective, multicenter cohort study was conducted in patients with pT1b EAC treated with endoscopic resection and/or surgery between 1989 and 2016. The primary end point was presence of LNM in surgical resection specimens or detection of metastases during follow-up. All resection specimens were histologically reassessed by specialist gastrointestinal pathologists. Subdistribution hazard regression analysis was used to develop the prediction model. The discriminative ability of this model was assessed using the c-statistic. RESULTS: 248 patients with pT1b EAC were included. Metastases were seen in 78 patients, and the 5-year cumulative incidence was 30.9 % (95 % confidence interval [CI] 25.1 %-36.8 %). The risk of metastases increased with submucosal invasion depth (subdistribution hazard ratio [SHR] 1.08, 95 %CI 1.02-1.14, for every increase of 500 µm), lymphovascular invasion (SHR 2.95, 95 %CI 1.95-4.45), and for larger tumors (SHR 1.23, 95 %CI 1.10-1.37, for every increase of 10 mm). The model demonstrated good discriminative ability (c-statistic 0.81, 95 %CI 0.75-0.86). CONCLUSIONS: A third of patients with pT1b EAC experienced metastases within 5 years. The probability of developing post-resection metastases was estimated with a personalized predicted risk score incorporating tumor invasion depth, tumor size, and lymphovascular invasion. This model requires external validation before implementation into clinical practice.

Tissue Systems Pathology Test Objectively Risk Stratifies Barrett's Esophagus Patients With Low-Grade Dysplasia.

INTRODUCTION: Low-grade dysplasia (LGD) is the best predictor of neoplastic progression in Barrett's esophagus (BE). Most LGD cases are downstaged to nondysplastic (ND) BE on expert pathologist review, which is prone to interobserver variation and not widely available. Recent studies indicate that a risk prediction assay (TissueCypher) risk stratifies patients with NDBE for neoplastic progression. We aimed to investigate whether this risk prediction assay predicts neoplastic progression in BE patients with LGD. METHODS: A blinded, retrospective cohort study was derived from the screening cohort of a randomized controlled trial of SURveillance vs RadioFrequency ablation for BE patients with LGD. Hematoxylin and eosin and p53 immunohistochemistry slides from the first endoscopy with LGD were independently reviewed by 3 expert pathologists and tested by the risk prediction assay. Revision diagnoses of NDBE were considered low risk, although indefinite for dysplasia, and LGD were considered high risk for progression. RESULTS: A total of 155 BE patients (123 men), mean age 61 ± 10 years, were analyzed. Thirty-four patients (22%) progressed to high-grade dysplasia/esophageal adenocarcinoma (median time 2.4 years) and 121 did not progress (median high-grade dysplasia/esophageal adenocarcinoma-free surveillance 7.9 years). The risk prediction assay sensitivity was 68% vs 76% for the 3 pathologists, and specificity was 79% vs 64%-77.0% for the pathologists. The assay detected 50%-56% of progressors that were downstaged to NDBE by the pathologists. DISCUSSION: The risk prediction assay provided significant risk stratification in BE patients with LGD and identified progressors that the experts downstaged to NDBE. This objective assay provides an effective solution to the lack of standardization of expert pathology review of LGD.

Patients With Barrett's Esophagus and Confirmed Persistent Low-Grade Dysplasia Are at Increased Risk for Progression to Neoplasia.

BACKGROUND & AIMS: For patients with Barrett's esophagus, the diagnosis of low-grade dysplasia (LGD) is subjective, and reported outcomes vary. We analyzed data from a multicenter study of endoscopic therapy to identify factors associated with progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in patients with LGD of the esophagus. METHODS: We performed a retrospective analysis of data from 255 patients with a primary diagnosis of LGD (78% men; mean age, 63 years) who participated in a randomized controlled trial of surveillance vs radiofrequency ablation in Europe. Three expert pathologists independently reviewed baseline and subsequent LGD specimens. The presence and degree of dysplasia was separately recorded for each biopsy and classified according to the Vienna Classification system. The primary end point was development of HGD or EAC. We performed univariate logistic regression analyses to assess the association between outcomes and factors such as number of pathologists confirming LGD, multifocality of LGD, and persistence of LGD over time. RESULTS: Of the 255 patients, 45 (18%) developed HGD or EAC during a median 42-month follow-up period (interquartile range, 25-61 months); patients were examined by a median 4 endoscopies (interquartile range, 3-6 endoscopies). The number of pathologists confirming LGD was strongly associated with progression to neoplasia; risk for progression increased greatly when all 3 pathologists agreed on LGD (odds ratio, 47.14; 95% confidence interval, 13.10-169.70). When LGD was detected at baseline and confirmed by a subsequent endoscopy, the odds for progression to neoplasia also increased greatly (odds ratio, 9.28; 95% confidence interval, 4.39-19.64). Multifocal LGD was not significantly associated with progression to neoplasia. CONCLUSIONS: The number of pathologists confirming LGD and persistence of LGD over time increase risk for development of HGD or EAC in patients with Barrett's esophagus and LGD. These simple, readily available variables can help stratify risk and select patients for prophylactic ablation therapy.

Improved diagnostic stratification of digitised Barrett's oesophagus biopsies by p53 immunohistochemical staining.

AIMS: Interobserver agreement for dysplasia in Barrett's oesophagus (BO) is low, and guidelines advise expert review of dysplastic cases. The aim of this study was to assess the added value of p53 immunohistochemistry (IHC) for the homogeneity within a group of dedicated gastrointestinal (GI) pathologists. METHODS AND RESULTS: Sixty-single haematoxylin and eosin (HE) slide referral BO cases [20 low-grade dysplasia (LGD); 20 high-grade dysplasia (HGD); and 20 non-dysplastic BO reference cases] were digitalised and independently assessed twice in random order by 10 dedicated GI pathologists. After a 'wash-out' period, cases were reassessed with the addition of a corresponding p53 IHC slide. Outcomes were: (i) proportion of 'indefinite for dysplasia' (IND) diagnoses; (ii) interobserver agreement; and (iii) diagnostic accuracy as compared with a consensus 'gold standard' diagnosis defined at an earlier stage by five core expert BO pathologists after their assessment of this case set. Addition of p53 IHC decreased the mean proportion of IND diagnoses from 10 of 60 to eight of 60 (P = 0.071). Mean interobserver agreement increased significantly from 0.45 to 0.57 (P = 0.0021). The mean diagnostic accuracy increased significantly from 72% to 82% (P = 0.0072) after p53 IHC addition. CONCLUSION: Addition of p53 IHC significantly improves the histological assessment of BO biopsies, even within a group of dedicated GI pathologists. It decreases the proportion of IND diagnoses, and increases interobserver agreement and diagnostic accuracy. This justifies the use of accessory p53 IHC within our upcoming national digital review panel for BO biopsy cases.

Prognostic Value of Pretreatment Pathological Tumor Extent in Patients Treated With Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal or Junctional Cancer.

OBJECTIVE: We aimed to determine pretreatment pathological tumor extent in the resection specimen after neoadjuvant chemoradiotherapy (nCRT) and to assess its prognostic value in patients with esophageal cancer. METHODS: Patients with esophageal cancer, treated with nCRT plus surgery were included (2003-2011). Pretreatment pathological T-stage (prepT-stage) and N-stage (prepN-stage) were estimated based on the extent of regressional changes and residual tumor cells in the resection specimen. Interobserver agreement was determined between 3 pathologists. The prognostic performance of prepT-stage and prepN-stage was scored using the difference in Akaike information criterion (ΔAIC). PrepN-stage and posttreatment pathological N-stage (ypN-stage) were combined to determine the effect of nodal sterilization on prognosis. RESULTS: Overall concordance for prepT-stage and prepN-stage was 0.69 and 0.84, respectively. Prognostic strength of prepT-stage was similar to clinical T-stage and worse compared with ypT-stage (ΔAIC 1.3 versus 2.0 and 8.9, respectively). In contrast, prognostic strength of prepN-stage was better than cN-stage and similar to ypN-stage (ΔAIC 17.9 versus 6.2 and 17.2, respectively). PrepN+ patients who become ypN0 after nCRT have a worse survival compared with prepN0 patients, with a five year overall survival of 51% versus 68%, P = 0.019, respectively. CONCLUSIONS: PrepT-stage and prepN-stage can be estimated reproducibly. Prognostic strength of prepT-stage is comparable with clinical T-stage, whereas prepN-stage is better than cN-stage. PrepN+ patients who become ypN0 after nCRT have a worse survival compared with prepN0 patients. Pretreatment pathological staging should be considered useful as a new staging parameter for esophageal cancer and could also be of interest for other tumor types.

Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II).

OBJECTIVE: Focal endoscopic resection (ER) followed by radiofrequency ablation (RFA) safely and effectively eradicates Barrett's oesophagus (BO) containing high-grade dysplasia (HGD) and/or early cancer (EC) in smaller studies with limited follow-up. Herein, we report long-term outcomes of combined ER and RFA for BO (HGD and/or EC) from a single-arm multicentre interventional study. DESIGN: In 13 European centres, patients with BO ≤ 12 cm with HGD and/or EC on 2 separate endoscopies were eligible for inclusion. Visible lesions (<2 cm length; <50% circumference) were removed with ER, followed by serial RFA every 3 months (max 5 sessions). Follow-up endoscopy was scheduled at 6 months after the first negative post-treatment endoscopic control and annually thereafter. OUTCOMES: complete eradication of neoplasia (CE-neo) and intestinal metaplasia (CE-IM); durability of CE-neo and CE-IM (once achieved) during follow-up. Biopsy and resection specimens underwent centralised pathology review. RESULTS: 132 patients with median BO length C3M6 were included. After entry-ER in 119 patients (90%) and a median of 3 RFA (IQR 3-4) treatments, CE-neo was achieved in 121/132 (92%) and CE-IM in 115/132 patients (87%), per intention-to-treat analysis. Per-protocol analysis, CE-neo and CE-IM were achieved in 98% and 93%, respectively. After a median of 27 months following the first negative post-treatment endoscopic control, neoplasia and IM recurred in 4% and 8%, respectively. Mild-to-moderate adverse events occurred in 25 patients (19%); all managed conservatively or endoscopically. CONCLUSIONS: In patients with early Barrett's neoplasia, intensive multimodality endotherapy consisting of ER combined with RFA is safe and highly effective, and the treatment effect appears to be durable during mid-term follow-up. TRIAL REGISTRATION NUMBER: NTR 1211, http://www.trialregister.nl.

Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: a prospective cohort study.

OBJECTIVE: The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. METHODS: In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. RESULTS: A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). CONCLUSIONS: A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.

Aberrant TP53 detected by combining immunohistochemistry and DNA-FISH improves Barrett's esophagus progression prediction: a prospective follow-up study.

Barrett's esophagus (BE) goes through a sequence of low grade dysplasia (LGD) and high grade dysplasia (HGD) to esophageal adenocarcinoma (EAC). The current gold standard for BE outcome prediction, histopathological staging, can be unreliable. TP53 abnormalities may serve as prognostic biomarkers. TP53 protein accumulation detected by immunohistochemistry (IHC) indirectly assesses TP53 mutations. DNA fluorescent in situ hybridization (FISH) on brush cytology specimens directly evaluates gene locus loss. We evaluated if IHC and FISH are complementary tools to assess TP53 abnormalities and tested their prognostic value in a long-term prospective follow-up of a BE cohort. TP53 IHC on tissue sections and FISH on brush cytology specimens were evaluated for 116 BE patients with respect to the different histological stages. The TP53 abnormalities were further studied in a panel of cell lines representative of the Barrett's carcinogenic sequence. For 91patients, the predictive value of TP53 abnormalities with respect to progression to HGD/EAC was tested after long term follow-up. The frequency of IHC and FISH TP53 abnormalities increased significantly with increasing histological stage (P < 0.001, Chi(2) -test). Combining the techniques detected TP53 abnormalities in 100% of patients with LGD, HGD, and EAC. Multivariate analysis showed that IHC (hazard ratio: 17, 95% CI: 3.2-96, P = 0.001) and FISH (hazard ratio: 7.3, 95% CI: 1.3-41, P = 0.02) were both independent significant predictors of progression. Combining FISH and IHC in assessing TP53 abnormalities leads to an increased detection rate of TP53 aberrations and improved accuracy for predicting BE progression.

Barrett's oesophagus patients with low-grade dysplasia can be accurately risk-stratified after histological review by an expert pathology panel.

OBJECTIVE: Reported malignant progression rates for low-grade dysplasia (LGD) in Barrett's oesophagus (BO) vary widely. Expert histological review of LGD is advised, but limited data are available on its clinical value. This retrospective cohort study aimed to determine the value of an expert pathology panel organised in the Dutch Barrett's Advisory Committee (BAC) by investigating the incidence rates of high-grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC) after expert histological review of LGD. DESIGN: We included all BO cases referred to the BAC for histological review of LGD diagnosed between 2000 and 2011. The diagnosis of the expert panel was related to the histological outcome during endoscopic follow-up. Primary endpoint was development of HGD or OAC. RESULTS: 293 LGD patients (76% men; mean 63 years±11.9) were included. Following histological review, 73% was downstaged to non-dysplastic BO (NDBO) or indefinite for dysplasia (IND). In 27% the initial LGD diagnosis was confirmed. Endoscopic follow-up was performed in 264 patients (90%) with a median follow-up of 39 months (IQR 16-72). For confirmed LGD, the risk of HGD/OAC was 9.1% per patient-year. Patients downstaged to NDBO or IND had a malignant progression risk of 0.6% and 0.9% per patient-year, respectively. CONCLUSIONS: Confirmed LGD in BO has a markedly increased risk of malignant progression. However, the vast majority of patients with community LGD will be downstaged after expert review and have a low progression risk. Therefore, all BO patients with LGD should undergo expert histological review of the diagnosis for adequate risk stratification.

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).

The impact of PNPLA3 (rs738409 C>G) polymorphisms on liver histology and long-term clinical outcome in chronic hepatitis B patients.

BACKGROUND & AIMS: We aimed to assess the association between the patatin-like phospholipase domain-containing-3 (PNPLA3) I148M polymorphism, liver histology and long-term outcome in chronic hepatitis B (CHB) patients. METHODS: We enrolled 531 consecutive treatment naïve CHB patients diagnosed from 1985 to 2012 with an available liver biopsy for reassessment, and sample for genetic testing. Data on all-cause mortality and hepatocellular carcinoma (HCC) at long-term follow-up were obtained from national database registries. RESULTS: The prevalence of steatohepatitis increased with PNPLA3 CC (14%), CG (20%) and GG (43%) (P < 0.001). The association was altered by both gender (P = 0.010) and overweight (P = 0.015): the effect of PNPLA3 on steatohepatitis was most pronounced among non-overweight females (adjusted OR 13.4, 95%CI: 3.7-51.6, P < 0.001), and non-overweight males (adjusted OR 2.4, 95%CI: 1.4-4.3, P = 0.002). Furthermore, PNPLA3 GG genotype was associated with iron depositions (OR 2.8, 95%CI: 1.2-6.4, P = 0.014) and lobular inflammation (OR 2.2, 95%CI: 1.1-4.5, P = 0.032), but not with advanced fibrosis (OR 1.1, 95%CI: 0.7-1.8, P = 0.566). The median follow-up was 10.1 years (interquartile range 5.6 - 15.8), during which 13 patients developed HCC and 28 died. Steatohepatitis was associated with all-cause mortality [Hazard ratio (HR) 3.1, 95%CI: 1.3-7.3, P = 0.006] and HCC (HR 2.8, 95%CI: 0.9-9.2, P = 0.078), but no significant association was observed for PNPLA3. CONCLUSIONS: In this cohort of biopsied CHB patients, PNPLA3 was independently associated with steatosis, steatohepatitis, lobular inflammation and iron depositions, but not with advanced fibrosis, HCC development or all-cause mortality. The effect of PNPLA3 on steatohepatitis was particularly pronounced among female patients without severe overweight.

Prolonged time to surgery after neoadjuvant chemoradiotherapy increases histopathological response without affecting survival in patients with esophageal or junctional cancer.

OBJECTIVE: To determine the relation between time to surgery (TTS) after neoadjuvant chemoradiotherapy (nCRT) and pathologically complete response (pCR), surgical outcome, and survival in patients with esophageal cancer. BACKGROUND: Standard treatment for potentially curable esophageal cancer is nCRT plus surgery after 4 to 6 weeks. In rectal cancer patients, evidence suggests that prolonged TTS is associated with a higher pCR rate and possibly with better survival. METHODS: We identified patients treated with nCRT plus surgery for esophageal cancer between 2001 and 2011. TTS (last day of radiotherapy to day of surgery) varied mainly for logistical reasons. Minimal follow-up was 24 months. The effect of TTS on pCR rate, postoperative complications, and survival was determined with (ordinal) logistic, linear, and Cox regression, respectively. RESULTS: In total, 325 patients were included. Median TTS was 48 days (p25-p75=40-60). After 45 days, TTS was associated with an increased probability of pCR [odds ratio (OR)=1.35 per additional week of TSS, P=0.0004] and a small increased risk of postoperative complications (OR=1.20, P<0.001). Prolonged TTS had no effect on disease-free and overall survivals (HR=1.00 and HR=1.06 per additional week of TSS, P=0.976 and P=0.139, respectively). CONCLUSIONS: Prolonged TTS after nCRT increases the probability of pCR and is associated with a slightly increased probability of postoperative complications, without affecting disease-free and overall survivals. We conclude that TTS can be safely prolonged from the usual 4 to 6 weeks up to at least 12 weeks, which facilitates a more conservative wait-and-see strategy after neoadjuvant chemoradiotherapy to be tested.

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.

Familial clustering of Barrett's esophagus and esophageal adenocarcinoma in a European cohort.

BACKGROUND & AIMS: Up to 7% of cases of Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC) in the United States occur in family clusters. We identified first-degree and second-degree relatives of patients with BE and EAC to determine the extent of familial clustering in a European cohort and studied differences between familial and nonfamilial cases. METHODS: A questionnaire was sent to all patients diagnosed with BE or EAC from 2000-2011 at 3 hospitals in the Netherlands (n = 838). Diagnoses of affected relatives were confirmed by using the Dutch Pathology Registry. Familial statuses of BE were defined as definitive (≥1 first-degree or second-degree relative with BE or EAC), possible (≥1 reported relative with BE or esophageal cancer without histologic confirmation), unlikely (no family history), or unknown. RESULTS: A total of 603 patients with BE or EAC (71%) responded and were included in the analysis. Familial BE was definitive for 7% of cases (n = 39, 10% of first-degree relatives affected), possible for 6% (n = 36), unlikely for 49% (n = 297), and unknown for 38% (n = 231). Definitive cases of familial BE were younger at onset of heartburn and EAC diagnosis; their first-degree relatives more frequently had reflux symptoms and a prior upper endoscopy, compared with unlikely cases of familial BE. CONCLUSIONS: In a database analysis of patients diagnosed with BE or EAC in the Netherlands, 7% of cases of BE and EAC were familial. These cases have a younger average age of onset of reflux symptoms and diagnosis of EAC than unlikely familial cases. These findings may indicate that genetic factors contribute to BE susceptibility, with a possible central role of gastroesophageal reflux.

Remission of Barrett's esophagus with early neoplasia 5 years after radiofrequency ablation with endoscopic resection: a Netherlands cohort study.

BACKGROUND & AIMS: Radiofrequency ablation (RFA), with or without endoscopic resection effectively eradicates Barrett's esophagus (BE) containing high-grade intraepithelial neoplasia and/or early-stage cancer. We followed patients who received RFA for BE containing high-grade intraepithelial neoplasia and/or early-stage cancer for 5 years to determine the durability of treatment response. METHODS: We followed 54 patients with BE (2-12 cm), previously enrolled in 4 consecutive cohort studies in which they underwent focal endoscopic resection in case of visible lesions (n = 40 [72%]), followed by serial RFA every 3 months. Patients underwent high-resolution endoscopy with narrow-band imaging at 6 and 12 months after treatment and then annually for 5 years (median, 61 months; interquartile range, 53-65 months); random biopsy samples were collected from neosquamous epithelium and gastric cardia. After 5 years, endoscopic ultrasound and endoscopic resection of neosquamous epithelium were performed. Outcomes included sustained complete remission of neoplasia or intestinal metaplasia (IM), IM in gastric cardia, or buried glands in neosquamous epithelium. RESULTS: After 5 years, Kaplan-Meier analysis showed sustained complete remission of neoplasia and intestinal metaplasia in 90% of patients; neoplasia recurred in 3 patients and was managed endoscopically. Focal IM in the cardia was found in 19 of 54 patients (35%), in 53 of 1143 gastric cardia biopsies (4.6%). The incidence of IM of the cardia did not increase over time; and IM was diagnosed based on only a single biopsy in 89% of patients. Buried glands were detected in 3 of 3543 neosquamous epithelium biopsies (0.08%, from 3 patients). No endoscopic resection samples had buried glands. CONCLUSIONS: Among patients who have undergone RFA with or without endoscopic resection for neoplastic BE, 90% remain in remission at 5-year follow-up, with all recurrences managed endoscopically. This treatment approach is therefore an effective and durable alternative to esophagectomy; www.trialregister.nl number, NTR2938.

Surveillance of Barrett's esophagus and mortality from esophageal adenocarcinoma: a population-based cohort study.

OBJECTIVES: Barrett's esophagus (BE) is associated with an increased risk of developing esophageal adenocarcinoma (EAC). Patients with a known diagnosis of BE are usually advised to participate in an endoscopic surveillance program, but its clinical value is unproven. Our objective was to compare patients participating in a surveillance program for BE before EAC diagnosis with those not participating in such a program, and to determine predictive factors for mortality from EAC. METHODS: All patients diagnosed with EAC between 1999 and 2009 were identified in the nationwide Netherlands Cancer Registry. These data were linked to Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief, the Dutch Pathology Registry. Prior surveillance was evaluated, and multivariable Cox proportional hazards regression analysis was performed to identify predictors for all-cause mortality at 2-year and 5-year follow-up. RESULTS: In total, 9,780 EAC patients were included. Of these, 791 (8%) patients were known with a prior diagnosis of BE, of which 452 (57%) patients participated in an adequate endoscopic surveillance program, 120 (15%) patients in an inadequate program, and 219 (28%) patients had a prior BE diagnosis without participating. Two-year (and five-year) mortality rates were lower in patients undergoing adequate surveillance (adjusted hazard ratio (HR)=0.79, 95% confidence interval (CI)=0.64-0.92) when compared with patients with a prior BE diagnosis who were not participating. Other factors associated with lower mortality from EAC were lower tumor stage (stage I vs. IV, HR=0.19, 95% CI=0.16-0.23) and combining surgery with neoadjuvant chemo/radiotherapy (HR=0.66, 95% CI=0.58-0.76). CONCLUSIONS: Participation in a surveillance program for BE, but only if adequately performed, reduces mortality from EAC. Nevertheless, it remains to be determined whether such a program is cost-effective, as more than 90% of all EAC patients were not known to have BE before diagnosis.

Prognostic biomarkers in patients with resected cholangiocarcinoma: a systematic review and meta-analysis.

PURPOSE: Biomarkers for patients with resected cholangiocarcinoma (CC) can improve staging and may ultimately result in personalized medicine. Studies evaluating these biomarkers often have shown inconsistent results. We performed a systematic review and meta-analysis to investigate the prognostic value of all immunohistochemistry-based markers that have been evaluated in patients with resected CC. METHODS: In July 2013, we searched the two main medical literature databases: MEDLINE and EMBASE. We extracted hazard ratios (HRs) and associated 95% confidence intervals (CIs) from the identified studies and performed random-effects model meta-analyses on overall survival (OS) in accordance with preferred reporting items for systematic reviews and meta-analyses statement and reporting recommendations for tumor marker prognostic studies (REMARK) guidelines. RESULTS: A total of 73 studies, including 4,126 patients studying 77 individual biomarkers, met the inclusion criteria. Fourteen studies were graded with a low risk of bias. Biomarkers prognostic of OS in pooled analysis included fascin (HR 2.58; 95% CI 1.19-5.58), EGFR (HR 1.79; 95% CI 1.14-2.8), MUC1 (HR 2.52; 95% CI 1.49-4.26), MUC4 (HR 2.45; 95% CI 1.56-3.86), and p27 (HR 0.29; 95% CI 0.14-0.6). Other markers showed promising results in single studies, including HSP27, Akt, HDGF, MUC6, p16, p-4EBP1, S100A4, α-SMA, Keratin 903, and TROP2. CONCLUSIONS: Meta-analysis demonstrated that the biomarkers fascin, EGFR, MUC1, MUC4, and p27 are associated with survival in patients with resected CC. Future studies should validate these, and other promising biomarkers, and adhere to the REMARK guidelines.

Pseudo-buried Barrett's post radiofrequency ablation for Barrett's esophagus, with or without prior endoscopic resection.

BACKGROUND AND STUDY AIM: In our experience, biopsies from small residual islands of nonburied Barrett's mucosa after radiofrequency ablation (RFA) are occasionally reported by pathologists to contain "buried Barrett's" upon histological evaluation, despite the fact that these islands of columnar mucosa were visible endoscopically. The aim of this study was to evaluate the frequency of buried Barrett's in biopsies obtained from small residual Barrett's islands ( < 5 mm) sampled post-RFA, compared with biopsies from normal neosquamous epithelium. PATIENTS AND METHODS: Biopsies obtained from normal-appearing neosquamous epithelium and from small Barrett's islands ( < 5 mm) in 69 consecutive Barrett's patients treated with RFA were evaluated for the presence of buried columnar mucosa. RESULTS: A total of 2515 biopsies were obtained from neosquamous epithelium during follow-up post-RFA. Buried glands were found in 0.1 % of biopsies from endoscopically normal neosquamous epithelium. However, when small islands of columnar mucosa were biopsied, buried glands were detected in 21 % of biopsies. CONCLUSION: To avoid accidental sampling of small islands resulting in a false-positive histological diagnosis of buried Barrett's, thorough inspection should be performed before obtaining biopsies during post-RFA follow-up.

Narrow band imaging does not reliably predict residual intestinal metaplasia after radiofrequency ablation at the neo-squamo columnar junction.

BACKGROUND AND STUDY AIMS: After radiofrequency ablation (RFA) of Barrett's esophagus, it may be difficult to determine whether complete eradication of intestinal metaplasia at the neosquamocolumnar junction (neo-SCJ) in the cardia has been achieved. It is claimed that narrow band imaging (NBI) may predict the presence of intestinal metaplasia, which would enable immediate treatment. The aim of the current study was to evaluate whether inspection of the neo-SCJ with NBI after RFA results in reliable detection of intestinal metaplasia. PATIENTS AND METHODS: Patients with a normal-appearing neo-SCJ who were scheduled for RFA were included in the study. Two expert endoscopists obtained images from the neo-SCJ in overview (high resolution white light and NBI mode) and from four areas using NBI zoom, followed by corresponding biopsies. Four other blinded expert endoscopists evaluated the images for the presence of intestinal metaplasia and type of mucosal pattern (round, small tubular, large tubular, villous). Endpoints were sensitivity and specificity for identifying patients and areas with intestinal metaplasia. RESULTS: From 21 patients overview images from 21 neo-SCJs and NBI zoom images from 83 neo-SCJ areas were obtained. Intestinal metaplasia was present in five overview images (24 %) and nine zoom images (11 %). Using the overview images, sensitivity and specificity for identifying patients with intestinal metaplasia were 65 % (95 % confidence interval [CI] 38 - 86) and 46 % (95 %CI 33 - 60), respectively. For individual zoom images, sensitivity was 71 % (95 %CI 54 - 85) and specificity was 37 % (95 %CI 32 - 43). CONCLUSIONS: After RFA, endoscopic inspection of the neo-SCJ with NBI in overview or zoom does not reliably predict presence or absence of intestinal metaplasia.

Exogenous pigment in Peyer patches of children suspected of having IBD.

OBJECTIVES: The base of human Peyer patches of the terminal ileum has been noted to contain black granular pigment deposits, composed of titanium dioxide and aluminosilicate, which are food additives typically present in a Western diet, and pharmaceuticals. In the present study, we investigated the distribution of exogenous pigment throughout the gastrointestinal tract of children suspected of having inflammatory bowel disease (IBD), the correlation between their age and the presence and amount of pigment in Peyer patches, and its relation to pediatric IBD. METHODS: Biopsies (upper and lower gastrointestinal tract) from children suspected of having IBD who underwent endoscopy, were reassessed by a blinded, expert pathologist. The amount of pigment in biopsies was scored using a semiquantitative scale (range 0 to +++). RESULTS: A total of 151 children were included: 62 with Crohn disease (CD), 26 with ulcerative colitis, and 63 with non-IBD. In 63 children (42%), deposits of black pigment were found only in biopsies from the terminal ileum, located in Peyer patches. A significant correlation was found between increasing age and the amount of pigment (P = 0.004). Pigment deposits were found significantly less in the patients with CD compared with those in patients with ulcerative colitis and those with non-IBD (26% vs 62% and 49%, P = 0.002). CONCLUSIONS: These results provide support for the hypothesis that the amount of pigment, only present in Peyer patches in the terminal ileum, becomes denser with increasing age. Absence of pigment in Peyer patches in a higher number of patients with CD suggests that microparticles may have become involved in the inflammatory process, possibly because of disrupted autophagy.