Publications by authors named "Cees A Seldenrijk"

16 Publications

  • Page 1 of 1

Extension of early esophageal squamous cell neoplasia into ducts and submucosal glands and the role of endoscopic ablation therapy.

Gastrointest Endosc 2021 May 8. Epub 2021 May 8.

Dept. of Gastroenterology and Hepatology, St. Antonius Hospital, Nieuwegein, the Netherlands;; Dept. of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands;. Electronic address:

Background And Aims: Early esophageal squamous cell neoplasia (ESCN) is preferably treated with en-bloc endoscopic resection. Ablation might be an alternative for flat ESCN, but ESCN extension along the epithelial lining of ducts and submucosal glands (SMGs) might jeopardize ablation efficacy. Clinical studies suggest that local recurrence might arise from such buried ESCN niches after ablation. We studied human endoscopic resection specimens of ESCN to quantify ESCN extension into ducts/SMGs and performed a prospective porcine study to evaluate depth of radiofrequency ablation (RFA) and CryoBalloon ablation (CBA) into ducts/SMGs.

Methods: ESD specimens of flat-type ESCN from a Japanese (n=65) and Dutch cohort (n=14) were evaluated for presence and neoplastic involvement of ducts/SMGs. Twenty-seven pigs were treated with circumferential RFA (n=4), focal CBA (n=20), and focal RFA (n=3) with 4/60/9 treatment areas, respectively. After prespecified survival periods (0h/8h/2d/5d/28d), treatment areas were evaluated for uniformity and depth of ablation and affected SMGs.

Results: Neoplastic extension in ducts/SMGs was observed in the majority of lesions: 58% (38/65) in the Japanese and 64% (9/14) in the Dutch cohort. In the animal study, 33% (95% CI, 28-50) of SMGs were not affected after circumferential RFA, although the overlying epithelium was ablated. Focal RFA and CBA resulted in uniform ablations with effective treatment of all SMGs.

Conclusion: ESCN extends into ducts/SMGs in the majority of patients. In an animal model, focal RFA, and CBA effectively ablated SMGs, whereas circumferential RFA inadequately ablated SMGs. Given this potential reason for recurrence, endoscopic resection should remain standard of care.
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http://dx.doi.org/10.1016/j.gie.2021.04.028DOI Listing
May 2021

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

Endoscopy 2021 Feb 24. Epub 2021 Feb 24.

Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands.

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.
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http://dx.doi.org/10.1055/a-1399-4989DOI Listing
February 2021

Ascending Aortic Aneurysm Secondary to Isolated Noninfectious Ascending Aortitis.

J Clin Rheumatol 2019 Jun;25(4):186-194

Division of Rheumatology and Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA.

Isolated noninfectious ascending aortitis (I-NIAA) is increasingly diagnosed at histopathologic review after resection of an ascending aortic aneurysm. PubMed was searched using the term aortitis; publications addressing the issue were reviewed, and reference lists of selected articles were also reviewed. Eleven major studies investigated the causes of an ascending aortic aneurysm or dissection requiring surgical repair: the prevalence of noninfectious aortitis ranged from 2% to 12%. Among 4 studies of lesions limited to the ascending aorta, 47% to 81% of cases with noninfectious aortitis were I-NIAA, more frequent than Takayasu arteritis or giant cell arteritis. Because of its subclinical nature and the lack of "syndromal signs" as in Takayasu arteritis or giant cell arteritis, I-NIAA is difficult to diagnose before complications occur, such as an aortic aneurysm or dissection. Therefore, surgical specimens of dissected aortic tissue should always be submitted for pathologic review. Diagnostic certainty requires the combination of a standardized histopathologic and clinical investigation. This review summarizes the current knowledge on I-NIAA, followed by a suggested approach to diagnosis, management, and follow-up. An illustrative case of an uncommon presentation is also presented. More follow-up studies on I-NIAA are needed, and diagnosis and follow-up of I-NIAA may benefit from the development of diagnostic biomarkers.
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http://dx.doi.org/10.1097/RHU.0000000000000948DOI Listing
June 2019

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

Gastroenterology 2017 04 22;152(5):993-1001.e1. Epub 2016 Dec 22.

Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1053/j.gastro.2016.12.008DOI Listing
April 2017

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

Gut 2015 May 17;64(5):700-6. Epub 2014 Jul 17.

Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1136/gutjnl-2014-307278DOI Listing
May 2015

Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.

JAMA 2014 Mar;311(12):1209-17

Department of Gastroenterology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Importance: Barrett esophagus containing low-grade dysplasia is associated with an increased risk of developing esophageal adenocarcinoma, a cancer with a rapidly increasing incidence in the western world.

Objective: To investigate whether endoscopic radiofrequency ablation could decrease the rate of neoplastic progression.

Design, Setting, And Participants: Multicenter randomized clinical trial that enrolled 136 patients with a confirmed diagnosis of Barrett esophagus containing low-grade dysplasia at 9 European sites between June 2007 and June 2011. Patient follow-up ended May 2013.

Interventions: Eligible patients were randomly assigned in a 1:1 ratio to either endoscopic treatment with radiofrequency ablation (ablation) or endoscopic surveillance (control). Ablation was performed with the balloon device for circumferential ablation of the esophagus or the focal device for targeted ablation, with a maximum of 5 sessions allowed.

Main Outcomes And Measures: The primary outcome was neoplastic progression to high-grade dysplasia or adenocarcinoma during a 3-year follow-up since randomization. Secondary outcomes were complete eradication of dysplasia and intestinal metaplasia and adverse events.

Results: Sixty-eight patients were randomized to receive ablation and 68 to receive control. Ablation reduced the risk of progression to high-grade dysplasia or adenocarcinoma by 25.0% (1.5% for ablation vs 26.5% for control; 95% CI, 14.1%-35.9%; P < .001) and the risk of progression to adenocarcinoma by 7.4% (1.5% for ablation vs 8.8% for control; 95% CI, 0%-14.7%; P = .03). Among patients in the ablation group, complete eradication occurred in 92.6% for dysplasia and 88.2% for intestinal metaplasia compared with 27.9% for dysplasia and 0.0% for intestinal metaplasia among patients in the control group (P < .001). Treatment-related adverse events occurred in 19.1% of patients receiving ablation (P < .001). The most common adverse event was stricture, occurring in 8 patients receiving ablation (11.8%), all resolved by endoscopic dilation (median, 1 session). The data and safety monitoring board recommended early termination of the trial due to superiority of ablation for the primary outcome and the potential for patient safety issues if the trial continued.

Conclusions And Relevance: In this randomized trial of patients with Barrett esophagus and a confirmed diagnosis of low-grade dysplasia, radiofrequency ablation resulted in a reduced risk of neoplastic progression over 3 years of follow-up.

Trial Registration: trialregister.nl Identifier: NTR1198.
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http://dx.doi.org/10.1001/jama.2014.2511DOI Listing
March 2014

An unusual rectal mass.

Gastroenterology 2012 Sep 26;143(3):e16-e17. Epub 2012 Jul 26.

Department of Pathology, St. Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands.

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http://dx.doi.org/10.1053/j.gastro.2012.02.047DOI Listing
September 2012

Endoscopic trimodal imaging versus standard video endoscopy for detection of early Barrett's neoplasia: a multicenter, randomized, crossover study in general practice.

Gastrointest Endosc 2011 Feb 18;73(2):195-203. Epub 2010 Dec 18.

Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.

Background: Endoscopic trimodal imaging (ETMI) may improve detection of early neoplasia in Barrett's esophagus (BE). Studies with ETMI so far have been performed in tertiary referral settings only.

Objective: To compare ETMI with standard video endoscopy (SVE) for the detection of neoplasia in BE patients with an intermediate-risk profile.

Design: Multicenter, randomized, crossover study.

Setting: Community practice.

Patients And Methods: BE patients with confirmed low-grade intraepithelial neoplasia (LGIN) underwent both ETMI and SVE in random order (interval 6-16 weeks). During ETMI, BE was inspected with high-resolution endoscopy followed by autofluorescence imaging (AFI). All visible lesions were then inspected with narrow-band imaging. During ETMI and SVE, visible lesions were sampled followed by 4-quadrant random biopsies every 2 cm.

Main Outcome Measurements: Overall histological yield of ETMI and SVE and targeted histological yield of ETMI and SVE.

Results: A total of 99 patients (79 men, 63±10 years) underwent both procedures. ETMI had a significantly higher targeted histological yield because of additional detection of 22 lesions with LGIN/high-grade intraepithelial neoplasia (HGIN)/carcinoma (Ca) by AFI. There was no significant difference in the overall histological yield (targeted+random) between ETMI and SVE. HGIN/Ca was diagnosed only by random biopsies in 6 of 24 patients and 7 of 24 patients, with ETMI and SVE, respectively.

Limitations: Inspection, with high-resolution endoscopy and AFI, was performed sequentially.

Conclusion: ETMI performed in a community-based setting did not improve the overall detection of dysplasia compared with SVE. The diagnosis of dysplasia is still being made in a significant number of patients by random biopsies. Patients with a confirmed diagnosis of LGIN have a significant risk of HGIN/Ca. (

Clinical Trial Registration Number: ISRCTN91816824; NTR867.).
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http://dx.doi.org/10.1016/j.gie.2010.10.014DOI Listing
February 2011

[Fewer unnecessary appendectomies following ultrasonography and CT].

Ned Tijdschr Geneeskd 2010 ;154:A869

Sint Antonius ziekenhuis, Afd. Heelkunde, Nieuwegein, The Netherlands.

Objective: To evaluate the effect of the use of ultrasonography (US) and optional computed tomography (CT) or diagnostic laparoscopy on the percentage of unnecessary appendectomies in patients with suspected acute appendicitis.

Design: Prospective and comparison with a historical control group.

Method: Following the introduction of ultrasound imaging as an initial step, the outcomes in all patients presenting with suspected appendicitis in the emergency department were prospectively collected during a period of 18 months (July 2006-December 2007). Results were compared to retrospectively collected data on all patients who had undergone appendectomy for acute appendicitis in 2001, before the introduction of this imaging investigation.

Results: Of the 312 consecutive patients in the emergency department with suspected acute appendicitis, the condition was excluded in 51 patients following clinical and laboratory investigation. The diagnostic algorithm was applied in 239 of the 261 patients (92%). All of them had initial US, followed by additional CT in 75 patients (31%) and diagnostic laparoscopy in 12 patients (5%). Appendectomy was performed in 130 patients, and 8 (6%) of the appendices were shown to be healthy following pathological investigation. Before the implementation of preoperative imaging 36 of the 170 appendices (21%) were healthy. Following the introduction of imaging techniques in accordance with the guideline there was a significant reduction in the percentage of unnecessary appendectomies (21% versus 6%; p < 0,001). The complete supplementary diagnostic algorithm had a positive and negative predictive value of respectively 90% and 98% for acute appendicitis.

Conclusion: Structural implementation of US with optional CT and diagnostic laparoscopy in patients with suspected acute appendicitis resulted in a lower percentage of unnecessary appendectomies.
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June 2010

Histopathologic studies of the below-the-knee great saphenous vein after endovenous laser ablation.

Dermatol Surg 2009 Dec;35(12):1985-8

Mauritskliniek Nijmegen, Nijmegen, The Netherlands.

Background: There has been hesitation to use endovenous laser ablation (EVLA) for the treatment of incompetence of the below-the-knee great saphenous vein (GSV).

Objective: To assess early pathologic changes in the below-the-knee nonvaricose GSV and adjacent tissue after EVLA in legs scheduled for below-the-knee amputation.

Methods: The below-the-knee GSV in five patients was exposed to EVLA using 14-, 12-, and 10-watt laser power with continuous or intermittent laser exposure using a 600-nm core, bare tip fiber. Six segments (3 x 3 cm) of GSV with adjacent tissue were excised, examined histologically, and compared with non-laser-exposed parts of the vessel.

Results: Histologic evaluation revealed thermal damage of the intima and the internal part of the media. At the site of the laser tip, carbonization and necrosis was observed. Vascular perforation with subsequent perivascular bleeding was occasionally (<10%) seen in cases treated with 40 to 80 J/cm and in all cases treated with 110 to 200 J/cm. The saphenous nerve was not damaged.

Conclusion: Based on this histopathologic study, acute thermal damage of the below-the-knee GSV after EVLA was limited to the intima and the inner third of the media. No acute damage of perivascular nerve tissue was observed.
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http://dx.doi.org/10.1111/j.1524-4725.2009.01317.xDOI Listing
December 2009

The additional value of EUS-guided Tru-cut biopsy to EUS-guided FNA in patients with mediastinal lesions.

Gastrointest Endosc 2009 May 26;69(6):1045-51. Epub 2009 Feb 26.

Department of Gastroenterology, St Antonius Hospital, Nieuwegein, the Netherlands.

Background And Objective: EUS-guided FNA is a sensitive method to obtain cytologic specimens from solid lesions in close proximity to the GI tract. Although FNA provides cells for analysis, large-caliber Tru-cut biopsy (EUS-TCB) needles obtain samples that can be used for additional histopathologic analysis. We assessed the additional diagnostic yield of EUS-TCB in patients with solid mediastinal lesions in whom EUS-FNA was performed.

Patients And Design: In the period from July 2003 to July 2007, all patients with mediastinal lesions accessible to EUS-FNA and EUS-TCB were evaluated. In all patients, a mean of 3 passes of EUS-FNA was followed by EUS-TCB. Cytologic and histologic specimens were evaluated by 2 pathologists blinded for patient condition. A final diagnosis was obtained by combining all information present (EUS-FNA and EUS-TCB results, mediastinoscopy, bronchoscopy [if performed], and other investigations).

Results: The diagnostic accuracy of EUS-FNA, EUS-TCB, and the combination of both techniques was 93%, 90%, and 98%, respectively (not significant). In EUS-FNA-negative patients, EUS-TCB provided a final diagnosis in an additional 3 patients (5%). Malignant disease found by EUS-FNA could be specified by EUS-TCB in 15 patients (25% of patients). The granulomatous disease established by cytologic samples of clinically suspected tuberculosis could be specified by EUS-TCB in 2 patients (3%). In 1 patient (2%), both FNA and TCB were inconclusive.

Limitations: Retrospective study.

Conclusions: The diagnostic yield of EUS-FNA and EUS-TCB is comparable. We recommend limiting the use of EUS-TCB to specific cases in which EUS-FNA is not conclusive.
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http://dx.doi.org/10.1016/j.gie.2008.09.034DOI Listing
May 2009

The microanatomic location of metastatic breast cancer in sentinel lymph nodes predicts nonsentinel lymph node involvement.

Ann Surg Oncol 2008 May 6;15(5):1309-15. Epub 2008 Feb 6.

Department of Pathology, St Antonius Hospital, Nieuwegein, The Netherlands.

Background: The majority of sentinel node (SN) positive breast cancer patients do not have additional non-SN involvement and may not benefit from axillary lymph node dissection (ALND). Previous studies in melanoma have suggested that microanatomic localization of SN metastases may predict non-SN involvement. The present study was designed to assess whether these criteria might also be used to be more restrictive in selecting breast cancer patients who would benefit from an ALND.

Methods: A consecutive series of 357 patients with invasive breast cancer and a tumor-positive axillary SN, followed by an ALND, was reviewed. Microanatomic SN tumor features (subcapsular, combined subcapsular and parenchymal, parenchymal, extensive localization, multifocality, and the penetrative depth from the SN capsule) were evaluated for their predictive value for non-SN involvement.

Results: Non-SN metastases were found in 136/357 cases (38%). Microanatomic location and penetrative depth of SN metastases were significant predictors for non-SN involvement (<0.001); limited penetrative depth was associated with a low frequency of non-SN involvement with a minimal of 10%.

Conclusions: Microanatomic location and penetrative depth of breast cancer SN metastases predict non-SN involvement. However, based on these features no subgroup of patients could be selected with less than 10% non-SN involvement.
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http://dx.doi.org/10.1245/s10434-007-9803-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277442PMC
May 2008

Intraobserver and interobserver variability and spatial differences in histologic examination of carotid endarterectomy specimens.

J Vasc Surg 2007 Dec 22;46(6):1147-54. Epub 2007 Oct 22.

Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.

Introduction: Studies using histologic examination and protein analysis of atherosclerotic plaques are increasingly being performed, but reproducibility of plaque histology and variation of plaque composition among different parts of the plaque, which are key to reliability of these studies, are relatively unexplored. Therefore, this study investigated the intraobserver and interobserver variability of plaque histology and spatial variability in plaque composition.

Methods: Atherosclerotic plaques (n = 100) obtained during carotid endarterectomy were divided into 0.5-cm segments. Paraffin sections were stained and semiquantitatively analyzed (four categories: no, minor, moderate, and heavy) for fat, macrophages, smooth muscle cells, collagen, calcification, thrombus, and overall phenotype. First, to determine the intraobserver and interobserver reproducibility, two independent observers independently analyzed the plaques. Second, to investigate spatial variability in plaque composition, histologic appearances of the culprit lesions (0-segment) were compared with the histologic appearances of adjacent (+5 mm) and more distant (+10 mm) plaque segments of 30 specimens.

Results: The kappa values for intraobserver variability of fat, macrophages, smooth muscle cells, collagen, calcifications, thrombus, and overall phenotype were 0.83, 0.85, 0.71, 0.63, 0.81, 0.80, and 0.86, respectively, and kappa values for interobserver variability were 0.68, 0.74, 0.54, 0.59, 0.82, 0.75, and 0.71, respectively. Comparison of the histologic scorings of adjacent segments revealed a mean kappa of 0.40 (range, 0.33 to 0.60). When the culprit segment was compared with the more distant segment, the mean kappa was 0.24; however, in 91% of cases, the difference between the culprit segment and the distal segment was one category or less.

Conclusion: Semiquantitative analysis of carotid atherosclerotic plaque histology was well reproducible, both intraobserver and interobserver. Although variation between different plaque segments in histologic appearance was observed, differences were small in almost all cases. Variability in histologic examination needs to be taken into account in studies comparing plaque imaging with histopathology and plaque research studies.
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http://dx.doi.org/10.1016/j.jvs.2007.08.018DOI Listing
December 2007

Severe hepatic side effects of ezetimibe.

Clin Gastroenterol Hepatol 2006 Jul 22;4(7):908-11. Epub 2006 Jun 22.

Department of Gastroenterology, St. Antonius Hospital, Nieuwegein, The Netherlands.

Background And Aims: Ezetimibe was introduced recently as a new class of cholesterol-lowering drugs. Until now only limited increases of transaminase levels were reported.

Methods: We studied 2 patients with severe hepatic side effects of ezetimibe in a general community hospital.

Results: Ezetimibe may lead to 2 distinct types of severe hepatic side effects.

Conclusions: Ezetimibe may rarely cause hepatotoxicity, severe cholestatic hepatitis, or acute autoimmune hepatitis.
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http://dx.doi.org/10.1016/j.cgh.2006.04.014DOI Listing
July 2006

Age-related changes in plaque composition: a study in patients suffering from carotid artery stenosis.

Cardiovasc Pathol 2005 May-Jun;14(3):126-34

Laboratory of Experimental Cardiology, UMCU, Utrecht, The Netherlands.

Objective: The extent of atherosclerotic plaque burden and the incidence of atherosclerosis-related cardiovascular events accelerate with increasing age. The composition of the plaque is associated with plaque thrombosis and acute coronary occlusion. Surprisingly, however, the relation between advancing age and atherosclerotic plaque composition is still unclear. In the present study, we investigated the association between plaque characteristics and advancing age in a population of patients with haemodynamically significant carotid artery stenosis.

Methods: Patients (N=383), ages 39-89 years, underwent carotid endarterectomy (CEA). Morphometric analysis was performed on the dissected atherosclerotic plaques to study the prevalence of fibrous and atheromatous plaques. Picro sirius red, haematoxylin eosin, alfa actin and CD68 stainings were performed to investigate the extent of collagen, calcification, smooth muscle cells and macrophages in carotid plaques, respectively. The presence of metalloproteinases-2 and -9 was assessed by ELISA.

Results: With aging, a decrease in fibrous plaques and an increase in atheromatous plaques were observed. This was accompanied by an age-associated decrease in smooth muscle cell content in carotid plaques. Macrophage content slightly increased with age. In addition, total matrix metalloprotease (MMP)-2 was negatively and MMP-9 positively related with age. Differences in plaque phenotype were most prominent for the youngest age quartile compared with older age quartiles.

Conclusions: With increasing age, the morphology of atherosclerotic plaques from patients with carotid artery stenosis changes. Plaques become more atheromatous and contain less smooth muscle cells with increasing age. Local inflammation and MMP-9 levels slightly increased with age in plaques obtained from patients suffering from haemodynamically significant advanced atherosclerotic lesions.
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http://dx.doi.org/10.1016/j.carpath.2005.03.002DOI Listing
August 2005

Athero-express: differential atherosclerotic plaque expression of mRNA and protein in relation to cardiovascular events and patient characteristics. Rationale and design.

Eur J Epidemiol 2004 ;19(12):1127-33

Department of Vascular Surgery, University Medical Centre, Utrecht, the Netherlands.

In clinical practice, biological markers are not available to routinely assess the progression of atherosclerotic disease or the development of restenosis following endarterectomy or catheter based interventions. Endarterectomy procedures provide an opportunity to study mechanisms of restenosis and progression of atherosclerotic disease since atherosclerotic tissue is obtained. Athero-Express is an ongoing prospective study, initiated in 2002, with the objective to investigate the etiological value of plaque characteristics for long term outcome. Patients are included who undergo an endarterectomy of the carotid artery. At baseline blood is withdrawn, patients fill in an extensive questionnaire and diagnostic examinations are performed. Atherosclerotic plaques are freshly harvested, immunohistochemically stained and examined for the presence of macrophages, smooth muscle cells, collagen and fat. Parts of the atherosclerotic plaques are freshly frozen to study protease activity and protein and RNA expressions. Patients undergo a duplex follow up to assess procedural restenosis (primary endpoint) at 3 months, 1 year and 2 years. Secondary endpoints encompass major adverse cardiovascular events. In the future, the creation of this biobank with atherosclerotic specimen will allow the design of cross-sectional and follow up studies with the objective to investigate the expression of newly discovered genes and proteins and their interaction with patients and plaque characteristics in the progression of atherosclerotic disease. Objective is to include 1000-1200 patients in 5 years. In January 2004, 289 patients had been included. It is expected that 250 patients will be included yearly.
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http://dx.doi.org/10.1007/s10564-004-2304-6DOI Listing
April 2005