Filter-based cerebral embolic protection with transcatheter aortic valve implantation: the randomised MISTRAL-C trial.

AIMS: Our aim was to determine whether use of the filter-based Sentinel™ Cerebral Protection System (CPS) during transcatheter aortic valve implantation (TAVI) can affect the early incidence of new brain lesions, as assessed by diffusion-weighted magnetic resonance imaging (DW-MRI), and neurocognitive performance. METHODS AND RESULTS: From January 2013 to July 2015, 65 patients were randomised 1:1 to transfemoral TAVI with or without the Sentinel CPS. Patients underwent DW-MRI and extensive neurological examination, including neurocognitive testing one day before and five to seven days after TAVI. Follow-up DW-MRI and neurocognitive testing was completed in 57% and 80%, respectively. New brain lesions were found in 78% of patients with follow-up MRI. Patients with the Sentinel CPS had numerically fewer new lesions and a smaller total lesion volume (95 mm3 [IQR 10-257] vs. 197 mm3 [95-525]). Overall, 27% of Sentinel CPS patients and 13% of control patients had no new lesions. Ten or more new brain lesions were found only in the control cohort (in 20% vs. 0% in the Sentinel CPS cohort, p=0.03). Neurocognitive deterioration was present in 4% of patients with Sentinel CPS vs. 27% of patients without (p=0.017). The filters captured debris in all patients with Sentinel CPS protection. CONCLUSIONS: Filter-based embolic protection captures debris en route to the brain in all patients undergoing TAVI. This study suggests that its use can lead to fewer and overall smaller new brain lesions, as assessed by MRI, and preservation of neurocognitive performance early after TAVI. CLINICAL TRIAL REGISTRATION: Dutch trial register-ID: NTR4236. URL http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=mistral.

Sentinel node biopsy during thoracolaparoscopic esophagectomy for advanced esophageal cancer.

BACKGROUND: Omitting extensive lymph node dissection could reduce esophagectomy morbidity in patients without lymph node metastases. Sentinel node biopsy may identify abdominal or thoracic lymph node metastases, thereby differentiating treatment. Feasibility of this approach was investigated in Western European esophageal cancer patients with advanced disease, without lymph node metastases at diagnostic work-up. METHODS: The sentinel node biopsy was performed in eight esophageal cancer patients with cT1-3N0 disease. One day pre-operatively, Tc-99m-labeled nanocolloid was endoscopically injected around the tumor. Lymphoscintigraphy was performed 1 and 3 h after injection. All patients underwent robotic thoracolaparoscopic esophagectomy with two-field lymph node dissection. Intraoperatively, sentinel nodes were detected by gamma probe. The resection specimen was analyzed for remaining activity by scintigraphy and gamma probe. RESULTS: Visualization rates of lymphoscintigraphy 1 and 3 h after tracer injection were 88 and 100%, respectively. Intraoperative identification rate was 38%. Postoperative identification was possible in all patients using the gamma probe to analyze the resection specimen. In 5/8 patients, lymph node metastases were found at histopathology, none of which was detected by the sentinel node biopsy. No adverse events related to the sentinel node biopsy were observed. CONCLUSIONS: In our advanced esophageal cancer patients who underwent thoracolaparoscopic esophagectomy, the sentinel node biopsy did not predict lymph node status. Probably the real sentinel node could not be identified due to localization adjacent to the primary tumor or bypassing due to metastatic tumor involvement. Therefore, we consider the sentinel node biopsy not feasible in advanced esophageal cancer.

The Importance of a Minimal Tumor-Free Resection Margin in Locally Recurrent Rectal Cancer.

BACKGROUND: The importance of the circumferential resection margin has been demonstrated in primary rectal cancer, but the role of the minimal tumor-free resection margin in locally recurrent rectal cancer is unknown. OBJECTIVE: The purpose of this work was to evaluate the prognostic importance of a minimal tumor-free resection margin in locally recurrent rectal cancer. DESIGN: This was a single-institution, retrospective study. SETTINGS: This study was conducted in a tertiary referral hospital. PATIENTS: Based on the final pathology report, surgically treated patients with locally recurrent rectal cancer between 1990 and 2013 were divided into 4 groups: 1) tumor-free margins of >2 mm, 2) tumor-free margins of >0 to 2 mm, 3) microscopically involved margins, and 4) macroscopically involved margins. MAIN OUTCOME MEASURES: Local control and overall survival were the main outcome measures. RESULTS: A total of 174 patients with a median follow-up of 27 months (range, 0-144 months) were eligible for analysis. There was a significant difference in 5-year local re-recurrence-free survival in favor of 41 patients with tumor-free margins of >2 mm compared with 34 patients with tumor-free margins of >0 to 2 mm (80% vs 62%; p = 0.03) and a significant difference in 5-year overall survival (60% vs 37%; p = 0.01). The 5-year local re-recurrence-free and overall survival rates for 55 patients with microscopically involved margins were 28% and 16%, and for 20 patients with macroscopically involved margins the rates were 0% and 5%. On multivariable analysis, tumor-free margins of >0 to 2 mm were independently associated with higher re-recurrence rates (HR, 2.76 (95% CI, 1.06-7.16)) and poorer overall survival (HR, 2.57 (95% CI, 1.27-5.21)) compared with tumor-free margins of >2 mm. LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: Resection margin status is an independent prognostic factor for re-recurrence rate and overall survival in surgically treated, locally recurrent rectal cancer. In complete resections, patients with tumor-free resection margins of >0 to 2 mm have a higher re-recurrence rate and a poorer overall survival than patients with tumor-free resection margins of >2 mm.

Incidence and predictors of debris embolizing to the brain during transcatheter aortic valve implantation.

OBJECTIVES: The aim of this study was to identify variables associated with tissue fragment embolization during transcatheter aortic valve replacement (TAVR). BACKGROUND: Brain magnetic resonance imaging and transcranial Doppler studies have revealed that cerebrovascular embolization occurs frequently during TAVR. Embolized material may be r thrombotic, tissue derived, or catheter (foreign material) fragments. METHODS: A total of 81 patients underwent TAVR with a dual filter-based embolic protection device (Montage Dual Filter System, Claret Medical, Inc., Santa Rosa, California) deployed in the brachiocephalic trunk and left common carotid artery. Both balloon-expandable and self-expanding transcatheter heart valves (THVs) were used. Filters were retrieved after TAVR and sent for histopathological analysis. RESULTS: Overall, debris was captured in 86% of patients. Captured material varied in size from 0.1 to 9.0 mm. Thrombotic material was found in 74% of patients and tissue-derived debris in 63%. Tissue fragments were found more often with balloon-expandable THVs (79% vs. 56%; p = 0.05). The embolized tissue originated from the native aortic valve leaflets, aortic wall, or left ventricular myocardium. On multivariable logistic regression analysis, balloon-expandable THVs (odds ratio: 7.315; 95% confidence interval: 1.398 to 38.289; p = 0.018) and cover index (odds ratio: 1.141; 95% confidence interval: 1.014 to 1.283; p = 0.028) were independent predictors of tissue embolization. CONCLUSIONS: Debris is captured with filter-based embolic protection in the vast majority of patients undergoing TAVR. Tissue-derived material is found in 63% of cases and is more frequent with the use of balloon-expandable systems and more oversizing.

Low fecal calprotectin predicts sustained clinical remission in inflammatory bowel disease patients: a plea for deep remission.

BACKGROUND AND AIMS: Mucosal healing has become the treatment goal in patients with ulcerative colitis (UC) and Crohn's disease (CD). Whether low fecal calprotectin levels and histological healing combined with mucosal healing is associated with a further reduced risk of relapses is unknown. METHODS: Patients with CD, UC or inflammatory bowel disease-unclassified (IBD-U) scheduled for surveillance colonoscopy collected a stool sample prior to bowel cleansing. Only patients with mucosal healing (MAYO endoscopic score of 0) were included. Fecal calprotectin was measured using a quantitative enzyme-linked immunosorbent assay (R-Biopharm, Germany). Biopsies were obtained from four colonic segments, and histological disease severity was assessed using the Geboes scoring system. Patients were followed until the last outpatient clinic visit or the development of a relapse, which was defined as IBD-related hospitalization, surgery or step-up in IBD medication. RESULTS: Of the 164 patients undergoing surveillance colonoscopy, 92 patients were excluded due to active inflammation or missing biopsies. Of the remaining 72 patients (20 CD, 52 UC or IBD-U), six patients (8%) relapsed after a median follow-up of 11 months (range 5-15 months). Median fecal calprotectin levels at baseline were significantly higher for patients who relapsed compared with patients who maintained remission (284 mg/kg vs. 37 mg/kg. p < 0.01). Fecal calprotectin below 56 mg/kg was found to optimally predict absence of relapse during follow-up with 64% sensitivity, 100% specificity, 100% negative predictive value and 20% positive predictive value. The presence or absence of active inflammation determined by Geboes cut-off score of 3.1 was less strongly associated with the risk of relapse (64% sensitivity, 33% specificity, 9% negative predictive value and 92% positive predictive value. CONCLUSION: Low calprotectin levels identify IBD patients who remain in stable remission during follow-up.

No decrease in the rate of early or missed colorectal cancers after colonoscopy with polypectomy over a 10-year period: a population-based analysis.

BACKGROUND & AIMS: It is not clear whether the incidence of missed or early colorectal cancers (CRCs) has decreased over time. We compared the rates of missed or early CRC after polypectomy between 1996 and 2006, and aimed to identify risk factors for these. METHODS: We performed a population-based, case-control study linking data from the Dutch Pathology Registry with data from The Netherlands Cancer Registry. Of all patients with an incident CRC in 1996 and 2006, we identified whether colonic histology specimens were available in the preceding 3 years. Patients with early or missed CRC were defined as those with previous colonic histology in the 6 to 36 months preceding CRC diagnosis. We performed multivariate logistic regression analysis to identify factors associated with missed or early CRCs. RESULTS: CRC was diagnosed in 6941 patients in 1996 and in 10,963 patients in 2006. The proportion of patients with early or missed CRC was 1.7% of all CRC patients in 1996 and 2.3% in 2006 (P = .012). Early or missed CRCs had a lower tumor, nodal, and metastasis stage than regularly diagnosed CRCs (P < .001), but rate of survival, adjusted for TNM stage, did not differ. CRCs of the right colon and transverse colon and splenic flexure were associated with a missed or early CRC (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.80-3.05; and OR, 2.14; 95% CI, 1.49-3.08, respectively), as was male sex (OR, 1.31; 95% CI, 1.06-1.62). CONCLUSIONS: Based on an analysis of the Dutch population, there has been no decrease in the occurrence of missed or early CRCs over a 10-year period. Location in the right side of the colon was an independent risk factor for missed or early CRCs.

Impact of global Fxr deficiency on experimental acute pancreatitis and genetic variation in the FXR locus in human acute pancreatitis.

BACKGROUND: Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the pancreas, exhibits anti-inflammatory effects by inhibiting NF-κB activation and is implicated in maintaining intestinal barrier integrity and preventing bacterial overgrowth and translocation. Here we explore, with the aid of complementary animal and human experiments, the potential role of FXR in acute pancreatitis. METHODS: Experimental acute pancreatitis was induced using the CCK-analogue cerulein in wild-type and Fxr-/- mice. Severity of acute pancreatitis was assessed using histology and a semi-quantitative scoring system. Ileal permeability was analyzed in vitro by Ussing chambers and an in vivo permeability assay. Gene expression of Fxr and Fxr target genes was studied by quantitative RT-PCR. Serum FGF19 levels were determined by ELISA in acute pancreatitis patients and healthy volunteers. A genetic association study in 387 acute pancreatitis patients and 853 controls was performed using 9 tagging single nucleotide polymorphisms (SNPs) covering the complete FXR gene and two additional functional SNPs. RESULTS: In wild-type mice with acute pancreatitis, ileal transepithelial resistance was reduced and ileal mRNA expression of Fxr target genes Fgf15, SHP, and IBABP was decreased. Nevertheless, Fxr-/- mice did not exhibit a more severe acute pancreatitis than wild-type mice. In patients with acute pancreatitis, FGF19 levels were lower than in controls. However, there were no associations of FXR SNPs or haplotypes with susceptibility to acute pancreatitis, or its course, outcome or etiology. CONCLUSION: We found no evidence for a major role of FXR in acute human or murine pancreatitis. The observed altered Fxr activity during the course of disease may be a secondary phenomenon.

Distinct phenotypes of cardiac allograft vasculopathy after heart transplantation: a histopathological study.

INTRODUCTION: Long-term survival after heart transplantation (HTx) is hampered by cardiac allograft vasculopathy (CAV). Better understanding of the pathophysiological mechanisms of CAV might have considerable consequences for therapeutic approaches in the future. The aim of the present study was to investigate the histological phenotypes of CAV in relation with clinical patient characteristics. METHODS AND RESULTS: Coronary cross-sections from 51 HTx patients were obtained at autopsy. CAV was observed in 42 patients (82%). Three histological CAV phenotypes were identified (H-CAV 1-3). No CAV (H-CAV 0) is as seen in normal coronary arteries; intimal thickening consisting of a layer of longitudinal oriented smooth muscle cells. In H-CAV 1 to 3 a second intimal layer is formed, on top of the longitudinal oriented smooth muscle cell layer, with predominantly mononuclear inflammatory infiltrate in loose connective tissue (H-CAV 1), smooth muscle cells in different orientation (H-CAV 2), or a fibrotic intimal lesion (H-CAV 3). H-CAV type was significantly related with time after transplantation, age at transplantation, the amount of atherosclerotic disease and the occurrence of infection. In addition, morphometric analysis revealed that higher H-CAV types have a relatively larger intimal area, that is compensated for by expansive arterial remodeling of the artery. CONCLUSION: CAV in an ongoing process that can be classified into three different phenotypes; inflammatory lesions, lesions rich of smooth muscle cells and fibrotic lesions. Our results suggest that these phenotypes are related to time after transplantation, age at transplantation, the amount of atherosclerotic disease and the occurrence of infection.

Two young women with soft tissue tumours of the heart.

Primary cardiac sarcomas often strike young, healthy patients and tend to have a dismal prognosis. Because of limited experience, the heterogeneous nature of cardiac sarcomas and different treatment results of patients with malignant primary tumours of the heart, the role of heart transplantation should be weighed on a case-by-case basis.

Novel no-stop FLNA mutation causes multi-organ involvement in males.

Mutations in FLNA (Filamin A, OMIM 300017) cause X-linked periventricular nodular heterotopia (XL-PNH). XL-PNH-associated mutations are considered lethal in hemizygous males. However, a few males with unusual mutations (including distal truncating and hypomorphic missense mutations), and somatic mosaicism have been reported to survive past infancy. Two brothers had an atypical presentation with failure to thrive and distinct facial appearance including hypertelorism. Evaluations of these brothers and their affected cousin showed systemic involvement including severe intestinal malfunction, malrotation, congenital short bowel, PNH, pyloric stenosis, wandering spleen, patent ductus arteriosus, atrial septal defect, inguinal hernia, and vesicoureteral reflux. The unanticipated finding of PNH led to FLNA testing and subsequent identification of a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). Western blotting and qRT-PCR of patients' fibroblasts showed diminished levels of protein and mRNA. This FLNA mutation, the most distal reported so far, causes in females classical XL-PNH, but in males an unusual, multi-organ phenotype, providing a unique insight into the FLNA-associated phenotypes.

Analysis of aortic valve commissural fusion after support with continuous-flow left ventricular assist device.

OBJECTIVES: Continuous-flow left ventricular assist devices (cf-LVADs) may induce commissural fusion of the aortic valve leaflets. Factors associated with this occurrence of commissural fusion are unknown. The aim of this study was to examine histological characteristics of cf-LVAD-induced commissural fusion in relation to clinical variables. METHODS: Gross and histopathological examinations were performed on 19 hearts from patients supported by either HeartMate II (n = 17) or HeartWare (n = 2) cf-LVADs and related to clinical characteristics (14 heart transplantation, 5 autopsy). RESULTS: Eleven of the 19 (58%) aortic valves showed fusion of single or multiple commissures (total fusion length 11 mm [4-20] (median [interquartile range]) per valve), some leading to noticeable nodular displacements or considerable lumen diameter narrowing. Multiple fenestrations were observed in one valve. Histopathological examination confirmed commissural fusion, with varying changes in valve layer structure without evidence of inflammatory infiltration at the site of fusion. Commissural fusion was associated with continuous aortic valve closure during cf-LVAD support (P = 0.03). LVAD-induced aortic valve insufficiency developed in all patients with commissural fusion and in 67% of patients without fusion. Age, duration of cf-LVAD support and aetiology of heart failure (ischaemic vs dilated cardiomyopathy) were not associated with the degree of fusion. CONCLUSIONS: Aortic valve commissural fusion after support with cf-LVADs is a non-inflammatory process leading to changes in valve layer structure that can be observed in >50% of cf-LVAD patients. This is the first study showing that patients receiving full cf-LVAD support without opening of the valve have a significantly higher risk of developing commissural fusion than patients on partial support.

Hepatitis E virus: an underestimated opportunistic pathogen in recipients of allogeneic hematopoietic stem cell transplantation.

Hepatitis E virus (HEV) is increasingly acknowledged as a cause of hepatitis in healthy individuals as well as immunocompromised patients. Little is known of HEV infection in recipients of allogeneic hematopoietic stem cell transplantation (alloHSCT). Therefore, we set out to study the incidence and sequelae of HEV as a cause of hepatitis in a recent cohort of 328 alloHSCT recipients. HEV RNA was tested in episodes of liver enzyme abnormalities. In addition, HEV RNA and HEV serology were assessed pre- and post-alloHSCT. We found 8 cases (2.4%) of HEV infection, of which 5 had developed chronic HEV infection. Seroprevalence pre-alloHSCT was 13%. Four patients died with HEV viremia, with signs of ongoing hepatitis, having a median time of infection of 4.1 months. The 4 surviving patients cleared HEV after a median period of 6.3 months. One patient was diagnosed with HEV reactivation after a preceding infection prior to alloHSCT. Although the incidence of developing acute HEV post-alloHSCT is relatively low, the probability of developing chronic hepatitis in severely immunocompromised patients is high. Therefore, alloHSCT recipients should be screened pretransplantation by HEV serology and RNA. Furthermore, a differential diagnosis including hepatitis E is mandatory in all alloHSCT patients with severe liver enzyme abnormalities.

Histopathology of embolic debris captured during transcatheter aortic valve replacement.

BACKGROUND: Recent transcatheter aortic valve replacement studies have raised concerns about adverse cerebrovascular events. The etiopathology of the embolized material is currently unknown. METHODS AND RESULTS: A total of 40 patients underwent transcatheter aortic valve replacement with the use of a dual filter-based embolic protection device (Montage Dual Filter System, Claret Medical, Inc). Macroscopic material liberated during the transcatheter aortic valve replacement procedure was captured in the device filter baskets in 30 (75%) patients and sent for histopathologic analysis. The captured material varied in size from 0.15 to 4.0 mm. Amorphous calcified material (size, 0.55-1.8 mm) was identified in 5 patients (17%). In 8 patients (27%), the captured material (size, 0.25-4.0 mm) contained valve tissue composed of loose connective tissue (collagen and elastic fibers) with focal areas of myxoid stroma, with or without coverage by endothelial cells and intermixed with fibrin. In another 13 (43%) patients, collagenous tissue, which may represent elements of vessel wall and valvelike structures, was identified. In 9 patients (30%), thrombotic material was intermixed with neutrophils (size, 0.15-2.0 mm). Overall, thrombotic material was found in 52% of patients, and tissue fragments compatible with aortic valve leaflet or aortic wall origin were found in 52% (21/40) of patients. CONCLUSIONS: Embolic debris traveling to the brain was captured in 75% of transcatheter aortic valve replacement procedures where a filter-based embolic protection device was used. The debris consisted of fibrin, or amorphous calcium and connective tissue derived most likely from either the native aortic valve leaflets or aortic wall.

Adenomas in patients with inflammatory bowel disease are associated with an increased risk of advanced neoplasia.

BACKGROUND: It is still unclear whether inflammatory bowel disease (IBD) patients with adenomas have a higher risk of developing high-grade dysplasia (HGD) or colorectal cancer (CRC) than non-IBD patients with sporadic adenomas. We compared the risk of advanced neoplasia (AN, defined as HGD or CRC) in IBD patients with adenomas to IBD patients without adenomas and patients without IBD with adenomas. METHODS: IBD patients with a histological adenoma diagnosis (IBD + adenoma), age-matched IBD patients without adenoma (IBD-nonadenoma), and adenoma patients without IBD (nonIBD + adenoma) were enrolled in this study. Medical charts were reviewed for adenoma characteristics and development of AN. The endoscopic appearance of the adenomas was characterized as typical (solitary sessile or pedunculated) or atypical (all other descriptions). RESULTS: A total of 110 IBD + adenoma patients, 123 IBD-nonadenoma patients, and 179 nonIBD + adenoma patients were included. Mean duration of follow-up was 88 months (SD ±41). The 5-year cumulative risks of AN were 11%, 3%, and 5% in IBD + adenoma, IBD-nonadenoma, and nonIBD + adenoma patients, respectively (P < 0.01). In IBD patients atypical adenomas were associated with a higher 5-year cumulative risk of AN compared to IBD patients with typical adenomas (18% vs. 7%, P = 0.03). CONCLUSIONS: IBD patients with a histological diagnosis of adenoma have a higher risk of developing AN than adenoma patients without IBD and IBD patients without adenomas. The presence of atypical adenomas in particular was associated with this increased risk, although patients with typical adenomas were found to carry an additional risk as well.

Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer, a randomized controlled trial (ROBOT trial).

BACKGROUND: For esophageal cancer patients, radical esophagolymphadenectomy is the cornerstone of multimodality treatment with curative intent. Transthoracic esophagectomy is the preferred surgical approach worldwide allowing for en-bloc resection of the tumor with the surrounding lymph nodes. However, the percentage of cardiopulmonary complications associated with the transthoracic approach is high (50 to 70%).Recent studies have shown that robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RATE) is at least equivalent to the open transthoracic approach for esophageal cancer in terms of short-term oncological outcomes. RATE was accompanied with reduced blood loss, shorter ICU stay and improved lymph node retrieval compared with open esophagectomy, and the pulmonary complication rate, hospital stay and perioperative mortality were comparable. The objective is to evaluate the efficacy, risks, quality of life and cost-effectiveness of RATE as an alternative to open transthoracic esophagectomy for treatment of esophageal cancer. METHODS/DESIGN: This is an investigator-initiated and investigator-driven monocenter randomized controlled parallel-group, superiority trial. All adult patients (age ≥ 18 and ≤ 80 years) with histologically proven, surgically resectable (cT1-4a, N0-3, M0) esophageal carcinoma of the intrathoracic esophagus and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 112) with resectable esophageal cancer are randomized in the outpatient department to either RATE (n = 56) or open three-stage transthoracic esophageal resection (n = 56). The primary outcome of this study is the percentage of overall complications (grade 2 and higher) as stated by the modified Clavien-Dindo classification of surgical complications. DISCUSSION: This is the first randomized controlled trial designed to compare RATE with open transthoracic esophagectomy as surgical treatment for resectable esophageal cancer. If our hypothesis is proven correct, RATE will result in a lower percentage of postoperative complications, lower blood loss, and shorter hospital stay, but with at least similar oncologic outcomes and better postoperative quality of life compared with open transthoracic esophagectomy. The study started in January 2012. Follow-up will be 5 years. Short-term results will be analyzed and published after discharge of the last randomized patient. TRIAL REGISTRATION: Dutch trial register: NTR3291 ClinicalTrial.gov: NCT01544790.

Surveillance and follow-up strategies in patients with high-grade dysplasia in Barrett's esophagus: a Dutch population-based study.

OBJECTIVES: In patients with high-grade dysplasia (HGD) in Barrett's esophagus (BE), it is incompletely known which factors are associated with developing esophageal adenocarcinoma (EAC). We analyzed prior biopsy and follow-up strategies in a large nationwide population-based cohort of patients with HGD in BE, and identified predictors of EAC progression. METHODS: Prior biopsy records and follow-up evaluations were studied in patients with HGD in BE diagnosed between 1999 and 2008, using PALGA, a nationwide network and registry of histopathology and cytopathology in the Netherlands. Multivariate Cox proportional hazards regression analysis was performed to identify predictors for prevalent (≤ 6 months) and incident (> 6 months) EAC. RESULTS: In total, 827 patients with HGD in BE were included. Follow-up data after HGD diagnosis were available in 699 (85%) patients. In 249 (36%) of these patients, an EAC was detected (14.1 EACs per 100 person-years). The risk of prevalent EAC (n=177) was lower with previous surveillance (hazards ratio 0.7; 95% confidence interval 0.5-0.9), unifocal HGD (0.3;0.2-0.6), diagnosis in a university hospital (0.5;0.3-0.9), endoscopic resection (0.5;0.3-0.7), or ablation (0.0;0.0-0.3); and higher when patients were 65-75 years (1.5;1.04-2.04). After exclusion of prevalent EACs, the progression rate was 4.2 EACs per 100 person-years. The risk of progression to incident EAC (n = 72) was lower with previous surveillance (0.6;0.3-0.9) and ablation (0.2;0.0-0.8), and higher when > 75 years (3.8;2.0-7.2) or with an interval > 6 months between HGD diagnosis and first follow-up (e.g., 7-12 months 2.9;1.3-6.3). CONCLUSIONS: In this cohort of patients with HGD in BE, the EAC detection rate was 14.1 per 100 person-years and 4.2 per 100 person-years after excluding prevalent cases. The risk of both prevalent and incident EAC was reduced with previous surveillance and endoscopic treatment, while it was increased with older age.

Role of immunohistochemical markers in predicting progression of dysplasia to advanced neoplasia in patients with ulcerative colitis.

BACKGROUND: Although dysplasia is thought to be the precursor lesion in the development of colitis-associated colorectal cancer (CRC), a significant proportion of patients with ulcerative colitis (UC) and low-grade (LGD) or indefinite (IND) dysplasia remain cancer-free during endoscopic follow-up. There is a need for biomarkers that predict neoplastic progression. We studied the value of a series of immunohistochemical markers in UC patients with flat LGD or IND with regard to neoplastic progression. METHODS: Tissue samples were collected from 12 UC patients (six flat LGD, six IND) without progression and from 10 UC patients (eight flat LGD, two IND) with documented progression to HGD and/or CRC during a median of 25 and 23 months of colonoscopic follow-up, respectively. Immunohistochemistry using monoclonal antibodies was performed for p53, CD44, Ki67, AMACR, ß-catenin, cyclin D1, p21, and ALDH. Positive and negative staining patterns were compared for progression to advanced neoplasia. RESULTS: When patients showed coexpression of p53 and AMACR, 6/7 patients (86%) developed advanced neoplasia, compared to 4/15 patients (27%) without p53/AMACR coexpression (P = 0.02). Patients with p53/AMACR coexpression developed advanced neoplasia in a time period of 19 months (median, range 1-101) compared to 80 months (median, range 8-169) in patients without p53/AMACR coexpression (P = 0.14). Interestingly, in three patients with progression and previous dysplasia-negative biopsies, two out of three biopsies were p53-positive a median of 12 months (range 10-14) before the LGD/IND diagnosis. CONCLUSIONS: This study suggests a role for p53/AMACR coexpression as a potential marker of neoplastic progression in patients with UC.