Heterogeneity of debris captured by cerebral embolic protection filters during TAVI.

AIMS: The aim of this study was to investigate the total amount, size and heterogeneity of debris captured among different transcatheter valve types and while repositioning. METHODS AND RESULTS: A total of 328 patients who underwent transcatheter aortic valve implantation (TAVI) with the SENTINEL cerebral embolic protection (CEP) at our centre were eligible. Histopathological and semiquantitative analysis of captured debris was performed and data were entered into our prospective database. TAVI was performed with either the Evolut R/PRO (N=123), SAPIEN 3 (N=113) or Lotus valve (N=92). Capture of debris occurred in 98% of patients. Lotus TAVI resulted in more frequent foreign body material (62% vs 40% vs 47%, p=0.006), endothelium (49% vs 30% vs 16%, p<0.0005), calcified material (33% vs 12% vs 24%, p=0.001) and myocardial tissue (19% vs 11% vs 2%, p<0.0005) compared to SAPIEN 3 or Evolut R/PRO. Native (functional) bicuspid valves (OR 2.91, 95% CI: 1.20-7.03, p=0.02) and Lotus (OR 2.44, 95% CI: 1.14-5.24, p=0.02) were associated with the highest risk for dislodging particles ≥1,000 um. Valve repositioning was independently associated with larger amounts of debris (OR 2.96, 95% CI: 1.42-6.16, p=0.004). CONCLUSIONS: All THV platforms had similar amounts of captured debris. THV repositioning seemed to be associated with a higher risk for dislodging greater amounts of debris to the brain.

Complete filter-based cerebral embolic protection with transcatheter aortic valve replacement.

OBJECTIVES: To evaluate the value of left vertebral artery filter protection in addition to the current filter-based embolic protection technology to achieve complete cerebral protection during TAVR. BACKGROUND: The occurrence of cerebrovascular events after transcatheter aortic valve replacement (TAVR) has fueled concern for its potential application in younger patients with longer life expectancy. Transcatheter cerebral embolic protection (TCEP) devices may limit periprocedural cerebrovascular events by preventing macro and micro-embolization to the brain. Conventional filter-based TCEP devices cover three extracranial contributories to the brain, yet leave the left vertebral artery unprotected. METHODS: Patients underwent TAVR with complete TCEP. A dual-filter system was deployed in the brachiocephalic trunk and left common carotid artery with an additional single filter in the left vertebral artery. After TAVR all filters were retrieved and sent for histopathological evaluation by an experienced pathologist. RESULTS: Eleven patients received a dual-filter system and nine of them received an additional left vertebral filter. In the remaining two patients, the left vertebral filter could not be deployed. No periprocedural strokes occurred. We found debris in all filters, consisting of thrombus, tissue derived debris, and foreign body material. The left vertebral filter contained debris in an equal amount of patients as the Sentinel filters. The size of the captured particles was similar between all filters. CONCLUSIONS: The left vertebral artery is an important entry route for embolic material to the brain during TAVR. Selective filter protection of the left vertebral artery revealed embolic debris in all patients. The clinical value of complete filter-based TCEP during TAVR warrants further research.

Risk of post-colonoscopy colorectal cancer due to incomplete adenoma resection: A nationwide, population-based cohort study.

BACKGROUND: Most post-colonoscopy colorectal cancers (PC-CRCs) are thought to develop from missed or incompletely resected adenomas. AIMS: We aimed to assess the incidence rate of PC-CRC overall and per colorectal segment, as a proxy for PC-CRC due to incomplete adenoma resection, and to identify adenoma characteristics associated with these PC-CRCs. METHODS: We performed a nationwide, population-based cohort study, including all patients with a first colorectal adenoma between 2000-2010 in the Dutch Pathology Registry (PALGA). Outcomes were the incidence rate of PC-CRC overall and of PC-CRC in the same colorectal segment, occurring between six months and five years after adenoma resection. A multivariable Cox proportional hazard analysis was performed to identify factors associated with PC-CRCs in the same segment. RESULTS: We included 107,744 patients (mean age 63.4 years; 53.6% male). PC-CRC was detected in 1031 patients (0.96%) with an incidence rate of 1.88 per 1000 person years. PC-CRC in the same segment was found in 323 of 133,519 adenomas (0.24%) with an incidence rate of 0.56 per 1000 years of follow-up. High-grade dysplasia (hazard ratio (HR) 2.54, 95% confidence interval (CI) 1.99-3.25) and both villous (HR 2.63, 95% CI 1.79-3.87) and tubulovillous histology (HR 1.80, 95% CI 1.43-2.27) were risk factors for PC-CRC in the same segment. CONCLUSIONS: Approximately one-third of PC-CRCs are found in the same colorectal segment after adenoma resection and could therefore be a consequence of incomplete adenoma resection, occurring in one in 400 adenomas. The risk of PC-CRC in the same segment is increased in adenomas with high-grade dysplasia or (tubulo)villous histology.

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.

Adding preoperative radiotherapy plus cetuximab to perioperative chemotherapy for resectable esophageal adenocarcinoma: a single-center prospective phase II trial.

BACKGROUND: Local and systemic recurrence are important sources of treatment failure following surgical resection of esophageal adenocarcinoma. We hypothesized that adding preoperative cetuximab and radiotherapy (cetux-RT) to perioperative chemotherapy would increase treatment efficacy with acceptable toxicity. METHODS: In this prospective phase II trial, patients were treated with three cycles of epirubicin, cisplatin, and capecitabine (ECX), followed by cetux-RT. After surgery with curative intent, patients received three more cycles of ECX. Primary endpoints were efficacy, determined by histopathological complete response (pCR) rate, and safety, which was assessed with resectability rate. RESULTS: Of the 12 patients enrolled in this trial, six received at least one dose of cetux-RT. In five patients, cetux-RT was not started because of adverse events (AEs) related to preoperative chemotherapy; one patient had progressive disease. Addition of cetux-RT was well tolerated and did not interfere with the resectability rate (100%). However, the pCR rate was 0, and 50% of patients experienced serious adverse events (SAEs) postoperatively. CONCLUSION: With 12 patients enrolled, the lack of initial signs of efficacy and a high incidence of postoperative SAEs prompted us to end this study prematurely. Perioperative ECX was associated with considerable toxicity, and further treatment intensification is problematic.

Appendiceal spirochaetosis in children.

BACKGROUND: Acute appendicitis is a surgical emergency in which the appendix is surgically removed to prevent peritonitis due to perforation of the appendix. Depending on age and gender, up to 17% of removed appendices do not show the histopathological changes pathognomonic for acute appendicitis and are called 'pseudo-appendicitis'. Intestinal spirochaetes have been reported in up to 12.3% of these non-inflamed appendices obtained from adults. Although children carry the highest risk for acute appendicitis, not much is known on the prevalence of intestinal spirochaetes in children. The aim of this study was to determine whether there is an association between pseudo-appendicitis and appendiceal spirochaetosis in children. METHODS: Archival appendix specimens from paediatric patients (less than 18 years old) were obtained from two Dutch hospitals (acute appendicitis, n = 63; pseudo-appendicitis, n = 55; control appendices, n = 33) and microscopically analysed by H&E staining and spirochaete-specific immunohistochemistry and Brachyspira species specific real-time PCR. RESULTS: Five out of 142 appendices were found to be positive, all in male patients: one in the acute appendicitis group, two in the pseudo-appendicitis group and two in the control group. CONCLUSION: The results obtained do not provide evidence for a role of Brachyspira species infection in the aetiology of acute appendicitis in children.

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.