Incidence and Prediction of Unrelated Mortality After Successful Endoscopic Eradication Therapy for Barrett's Neoplasia.

BACKGROUND & AIMS: Follow-up (FU) strategies after endoscopic eradication therapy (EET) for Barrett's neoplasia do not consider the risk of mortality from causes other than esophageal adenocarcinoma (EAC). We aimed to evaluate this risk during long-term FU, and to assess whether the Charlson Comorbidity Index (CCI) can predict mortality. METHODS: We included all patients with successful EET from the nationwide Barrett registry in the Netherlands. Data were merged with National Statistics for accurate mortality data. We evaluated annual mortality rates (AMRs, per 1000 person-years) and standardized mortality ratio for other-cause mortality. Performance of the CCI was evaluated by discrimination and calibration. RESULTS: We included 1154 patients with a mean age of 64 years (±9). During median 59 months (p25-p75 37-91; total 6375 person-years), 154 patients (13%) died from other causes than EAC (AMR, 24.1; 95% CI, 20.5-28.2), most commonly non-EAC cancers (n = 58), cardiovascular (n = 31), or pulmonary diseases (n = 26). Four patients died from recurrent EAC (AMR, 0.5; 95% CI, 0.1-1.4). Compared with the general Dutch population, mortality was significantly increased for patients in the lowest 3 age quartiles (ie, age <71 years). Validation of CCI in our population showed good discrimination (Concordance statistic, 0.78; 95% CI, 0.72-0.84) and fair calibration. CONCLUSION: The other-cause mortality risk after successful EET was more than 40 times higher (48; 95% CI, 15-99) than the risk of EAC-related mortality. Our findings reveal that younger post-EET patients exhibit a significantly reduced life expectancy when compared with the general population. Furthermore, they emphasize the strong predictive ability of CCI for long-term mortality after EET. This straightforward scoring system can inform decisions regarding personalized FU, including appropriate cessation timing. (NL7039).

Impact of expert center endoscopic assessment of confirmed low grade dysplasia in Barrett's esophagus diagnosed in community hospitals.

BACKGROUND : The optimal management for patients with low grade dysplasia (LGD) in Barrett's esophagus (BE) is unclear. According to the Dutch national guideline, all patients with LGD with histological confirmation of the diagnosis by an expert pathologist (i. e. "confirmed LGD"), are referred for a dedicated re-staging endoscopy at an expert center. We aimed to assess the diagnostic value of re-staging endoscopy by an expert endoscopist for patients with confirmed LGD. METHODS : This retrospective cohort study included all patients with flat BE diagnosed in a community hospital who had confirmed LGD and were referred to one of the nine Barrett Expert Centers (BECs) in the Netherlands. The primary outcome was the proportion of patients with prevalent high grade dysplasia (HGD) or cancer during re-staging in a BEC. RESULTS : Of the 248 patients with confirmed LGD, re-staging in the BEC revealed HGD or cancer in 23 % (57/248). In 79 % (45/57), HGD or cancer in a newly detected visible lesion was diagnosed. Of the remaining patients, re-staging in the BEC showed a second diagnosis of confirmed LGD in 68 % (168/248), while the remaining 9 % (23/248) had nondysplastic BE. CONCLUSION : One quarter of patients with apparent flat BE with confirmed LGD diagnosed in a community hospital had prevalent HGD or cancer after re-staging at an expert center. This endorses the advice to refer patients with confirmed LGD, including in the absence of visible lesions, to an expert center for re-staging endoscopy.

Long-term outcomes after endoscopic treatment for Barrett's neoplasia with radiofrequency ablation ± endoscopic resection: results from the national Dutch database in a 10-year period.

OBJECTIVE: Radiofrequency ablation (RFA)±endoscopic resection (ER) is the preferred treatment for early neoplasia in Barrett's oesophagus (BE). We aimed to report short-term and long-term outcomes for all 1384 patients treated in the Netherlands (NL) from 2008 to 2018, with uniform treatment and follow-up (FU) in a centralised setting. DESIGN: Endoscopic therapy for early BE neoplasia in NL is centralised in nine expert centres with specifically trained endoscopists and pathologists that adhere to a joint protocol. Prospectively collected data are registered in a uniform database. Patients with low/high-grade dysplasia or low-risk cancer, were treated by ER of visible lesions followed by trimonthly RFA sessions of any residual BE until complete eradication of BE (CE-BE). Patients with ER alone were not included. RESULTS: After ER (62% of cases; 43% low-risk cancers) and median 1 circumferential and 2 focal RFA (p25-p75 0-1; 1-2) per patient, CE-BE was achieved in 94% (1270/1348). Adverse events occurred in 21% (268/1386), most commonly oesophageal stenosis (15%), all were managed endoscopically. A total of 1154 patients with CE-BE were analysed for long-term outcomes. During median 43 months (22-69) and 4 endoscopies (1-5), 38 patients developed dysplastic recurrence (3%, annual recurrence risk 1%), all were detected as endoscopically visible abnormalities. Random biopsies from a normal appearing cardia showed intestinal metaplasia (IM) in 14% and neoplasia in 0%. A finding of IM in the cardia was reproduced during further FU in only 33%, none progressed to neoplasia. Frequent FU visits in the first year of FU were not associated with recurrence risk. CONCLUSION: In a setting of centralised care, RFA±ER is effective for eradication of Barrett's related neoplasia and has remarkably low rates of dysplastic recurrence. Our data support more lenient FU intervals, with emphasis on careful endoscopic inspection. Random biopsies from neosquamous epithelium and cardia are of questionable value. NETHERLANDS TRIAL REGISTER NUMBER: NL7039.

The SpaTemp cohort: 168 nondysplastic Barrett's esophagus surveillance patients with and without progression to early neoplasia to evaluate the distribution of biomarkers over space and time.

The ReBus cohort is a matched nested case-control cohort of patients with nondysplastic (ND) Barrett's esophagus (BE) at baseline who progressed (progressors) or did not progress (nonprogressors) to high-grade dysplasia (HGD) or cancer. This cohort is constructed using the most stringent inclusion criteria to optimize explorative studies on biomarkers predicting malignant progression in NDBE. These explorative studies may benefit from expanding the number of cases and by incorporating samples that allow assessment of the biomarker over space (spatial variability) and over time (temporal variability). To (i) update the ReBus cohort by identifying new progressors and (ii) identify progressors and nonprogressors within the updated ReBus cohort containing spatial and temporal information. The ReBus cohort was updated by identifying Barrett's patients referred for endoscopic work-up of neoplasia at 4 tertiary referral centers. Progressors and nonprogressors with a multilevel (spatial) endoscopy and additional prior (temporal) endoscopies were identified to evaluate biomarkers over space and over time. The original ReBus cohort consisted of 165 progressors and 723 nonprogressors. We identified 65 new progressors meeting the same strict selection criteria, resulting in a total number of 230 progressors and 723 matched nonprogressors in the updated ReBus cohort. Within the updated cohort, 61 progressors and 107 nonprogressors (mean age 61 ± 10 years) with a spatial endoscopy (median level 3 [2-4]) were identified. 33/61 progressors and 50/107 nonprogressors had a median of 3 (2-4) additional temporal endoscopies. Our updated ReBus cohort consists of 230 progressors and 723 matched nonprogressors using the most strict selection criteria. In a subgroup of 168 Barrett's patients (the SpaTemp cohort), multiple levels have been sampled at baseline and during follow-up providing a unique platform to study spatial and temporal distribution of biomarkers in BE.

Endoscopic Resection Without Subsequent Ablation Therapy for Early Barrett's Neoplasia: Endoscopic Findings and Long-Term Mortality.

INTRODUCTION: After endoscopic resection (ER) of neoplasia in Barrett's esophagus (BE), it is recommended to ablate the remaining BE to minimize the risk for metachronous disease. However, we report long-term outcomes for a nationwide cohort of all patients who did not undergo ablation of the remaining BE after ER for early BE neoplasia, due to clinical reasons or performance status. METHODS: Endoscopic therapy for BE neoplasia in the Netherlands is centralized in 8 expert centers with specifically trained endoscopists and pathologists. Uniformity is ensured by a joint protocol and regular group meetings. We report all patients who underwent ER for a neoplastic lesion between 2008 and 2018, without further ablation therapy. Outcomes include progression during endoscopic FU and all-cause mortality. RESULTS: Ninety-four patients were included with mean age 74 (± 10) years. ER was performed for low-grade dysplasia (LGD) (10%), high-grade dysplasia (HGD) (25%), or low-risk esophageal adenocarcinoma (EAC) (65%). No additional ablation was performed for several reasons; in 73 patients (78%), the main argument was expected limited life expectancy. Median C2M5 BE persisted after ER, and during median 21 months (IQR 11-51) with 4 endoscopies per patient, no patient progressed to advanced cancer. Seventeen patients (18%) developed HGD/EAC: all were curatively treated endoscopically. In total, 29/73 patients (40%) with expected limited life expectancy died due to unrelated causes during FU, none of EAC. CONCLUSION: In selected patients, ER monotherapy with endoscopic surveillance of the residual BE is a valid alternative to eradication therapy with ablation.

Intensified Neoadjuvant Chemoradiotherapy for Patients with Potentially Resectable Esophageal Cancer: A Retrospective Cohort Study.

BACKGROUND: Neoadjuvant treatment consisting of five cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy), followed by esophagectomy, is the standard treatment for resectable esophageal cancer in The Netherlands. It remains unclear whether intensification of neoadjuvant therapy leads to better outcomes. This study analyzed the outcomes of intensified chemoradiotherapy. METHODS: We included patients who were deemed eligible for esophagectomy between January 2008 and December 2014. Neoadjuvant therapy consisted of six cycles of carboplatin (area under the curve = 2 mg/mL/min) and paclitaxel (50 mg/m2 of body surface area) and concurrent radiotherapy (50.4 Gy administered in 28 fractions of 1.8 Gy each, 5 days per week), followed by esophagectomy. RESULTS: Of the 176 patients included in this study, 73% underwent a resection. At a median follow-up of 29.3 months for the total cohort, median disease-free survival (DFS) was 22.5 months. DFS at 3 and 5 years was 42% and 36%, respectively, while the overall survival (OS) rates were 47% and 38%, respectively. In addition, the 5-year DFS and OS rates of our resection group were 44% and 48%, respectively. In 102 patients (58%), grade 3 or higher adverse events were observed, mainly hematological. The postoperative mortality rate within 30 days was 4%, and pathological complete response was achieved in 35% of patients. CONCLUSIONS: Intensification of neoadjuvant chemoradiotherapy for patients with potentially resectable esophageal cancer is well tolerated, yielding high pathological complete response rates, but adverse events occurred frequently, and survival compared with conventional neoadjuvant chemoradiotherapy seems similar. Therefore, intensification of neoadjuvant chemoradiotherapy should not be routinely used.

A comparison of the new ROTEM® sigma with its predecessor, the ROTEMdelta.

Thromboelastometry point-of-care coagulation testing facilitates optimised management of bleeding. Previous thromboelastometry systems required the blood sample and liquid reagents to be pipetted in several manual steps by trained personnel. The ROTEMsigma coagulation analyser is a fully automated point-of-care device. We aimed to assess the reference ranges of the new device and to compare the results with those of the predecessor device, the ROTEMdelta. We took blood from healthy volunteers and from hyper- or hypocoagulable patients; blood samples from healthy volunteers served to determine reference ranges for the most important parameters for the ROTEMsigma: CTEXTEM 48-61 s; A5EXTEM 30-51 mm; MCFEXTEM 54-70 mm; CTINTEM 138-174 s; MCFINTEM 51-67 mm and MCFFIBTEM 5-24 mm. We then used blood samples from patients to compare the results obtained between the old and the new device. We found a strong correlation between the same tests performed on two ROTEMsigma devices and between the ROTEMsigma and the ROTEMdelta with respect to the determination of thromboelastometry parameters of hyper- and hypocoagulable patients (all p < 0.001 and R > 0.8). Performance evaluation for the ROTEMsigma device showed very high precision (R > 0.99, p < 0.001). Our reference ranges can serve as an important aid for other hospitals using this new device.

Transition to adult diabetes care in Germany-High risk for acute complications and declining metabolic control during the transition phase.

OBJECTIVE: There is evidence that transition from pediatric to adult health care is frequently associated with deterioration of health in youths with type 1 diabetes (T1D). The aim of this study was to compare metabolic control, acute complications and microvascular complications in adolescents and young adults before and after transfer to an adult treatment center with respect to the time between first visit in the adult center and last visit in pediatric treatment. METHODS: All data were collected during routine care and retrieved from the German/Austrian DPV database. We analyzed data as of March 2017. RESULTS: We found 1283 young adults with available data of the last pediatric treatment year and the first year after transition to adult care. HbA1c increased significantly from 8.95% (74 mmol/mol) before to 9.20% (77 mmol/mol) in the first year after transition. Frequency of DKA with hospitalization (0.10-0.191 per annum, P < .0001) and severe hypoglycemia (0.23-0.46 per annum, P = .013) doubled during transition. Microvascular complications increased dramatically depending on the time between first visit in adult treatment and last visit in pediatric care. We could not find a significant correlation of this rise of microvascular complications to the duration of transition (short or long). CONCLUSION: This phase of life bears a high risk for detrimental outcome in young adults with T1D. Structured transition programs with case management are therefore needed to improve the transition process and outcomes.

Safety of endoscopic mucosal resection (EMR) of large non-pedunculated colorectal adenomas in the elderly.

BACKGROUND: Endoscopic mucosal resection (EMR) has been proven to be safe and effective for the treatment of colorectal adenomas. However, data are limited on the safety of this technique for large polyps and in elderly patients. Aims of our study were to examine the bleeding and perforation rates in patients with large non-pedunculated adenomas (≥20mm) and to evaluate the influence of size (≥40mm) and age (≥75 years) on the complication rates. METHODS: In this multicenter retrospective study, patients who underwent EMR of non-pedunculated adenomas ≥20mm between January 2012 and March 2016 were included. The demographics of the patients, the use of antithrombotic drugs, size of the polyps, type of resection, pathology report, occurrence of post-polypectomy bleeding, and perforation- and recurrence rate were collected. RESULTS: In 343 patients, 412 adenomas were removed. Eighty patients (23.3%) were ≥75 years of age, 138 polyps (33.5%) were ≥40mm. Bleeding complications were observed in 28 cases (6.8%) and were found significantly more frequent in adenomas ≥40mm, independent of the use of antithrombotic therapy. Five perforations (1.2%) were described, not related to the size of the polyp. There was no significant difference in complication rates between patients <75 years and patients ≥75 years. Bleeding complications rates were significantly higher in patients receiving double antithrombotic therapy. CONCLUSION: EMR is safe in elderly patients. EMR of adenomas of ≥40mm was associated with more bleeding complications. Future studies should address how the bleeding rates can be reduced in these patients, especially in those who use double antithrombotic treatment.

Fibrinogen supplementation ex vivo increasesclot firmness comparable to platelet transfusion in thrombocytopenia.

BACKGROUND: Fibrinogen concentrate can improve clot firmness and offers a better safety profile than platelet concentrates. Reduction or avoidance of blood transfusions represents a strategy to reduce associated risks. We investigated whether supplementation of fibrinogen concentrate ex vivo can compensate for clot strength as compared with platelet transfusion in vivo METHODS: One hundred patients in need of platelet transfusion (PT) were enrolled. Blood samples were collected immediately before PT and at 1 h and 24 h after PT. Fibrinogen concentrate was added to these citrated whole blood samples at concentrations of 50, 100, 200 and 400 mg kg-1 and the maximum clot firmness (MCF) was analysed using ROTEM thromboelastometry. RESULTS: Fibrinogen supplementation increased MCF significantly and dose-dependently before and after PT. The effect of fibrinogen concentrate (equivalent to doses of 100 and 200 mg kg-1) ex vivo was comparable to that of PT in vivo, whereas 400 mg kg-1 fibrinogen significantly improved MCF compared with PT (P < 0.001). CONCLUSIONS: Fibrinogen concentrate can match the effect of PT on MCF in thrombocytopenia. This potential alternative haemostatic intervention should be evaluated in clinical trials.

Ex vivo reversal of effects of rivaroxaban evaluated using thromboelastometry and thrombin generation assay.

BACKGROUND: In major bleeding events, the new direct oral anticoagulants pose a great challenge for physicians. The aim of the study was to test for ex vivo reversal of the direct oral anticoagulant rivaroxaban with various non-specific reversal agents: prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), recombinant activated factor VII (rFVIIa), and fibrinogen concentrate (FI). METHODS: Blood was obtained from healthy volunteers and from patients treated with rivaroxaban. Blood samples from healthy volunteers were spiked with rivaroxaban to test the correlation between rivaroxaban concentration and coagulation tests. Patient blood samples were spiked with various concentrations of the above-mentioned agents and analysed using thromboelastometry and thrombin generation. RESULTS: When added in vitro, rivaroxaban was significantly (P<0.05) correlated with ROTEM® thromboelastometry EXTEM (extrinsic coagulation pathway) clotting time (CT), time to maximal velocity (MaxV-t), and with all measured thrombin generation parameters. In vivo, CT, MaxV-t, lag time, and peak thrombin generation (Cmax) were significantly correlated with rivaroxaban concentrations. Regarding reversal of rivaroxaban, all tested agents significantly (P<0.05) reduced EXTEM CT, but to different extents: rFVIIa by 68%, aPCC by 47%, PCC by 17%, and FI by 9%. Only rFVIIa reversed EXTEM CT to baseline values. Both PCC (+102%) and aPCC (+232%) altered overall thrombin generation (area under the curve) and increased Cmax (+461% for PCC, +87.5% for aPCC). CONCLUSIONS: Thromboelastometry and thrombin generation assays do not favour the same reversal agents for rivaroxaban anticoagulation. Controlled clinical trials are urgently needed to establish doses and clinical efficacy of potential reversal agents. CLINICAL TRIAL REGISTRATION: EudracCT trial no. 213-00474-30.

Fibrinogen concentrate improves clot strength in patients with haematological malignancies requiring platelet transfusion.

BACKGROUND: Patients with bone marrow failure secondary to chemotherapy often develop thrombocytopenia and require platelet transfusion. Fibrinogen plays an important role in platelet aggregation and the establishment of the primary haemostatic plug. OBJECTIVES: To compare the effects of in vivo platelet transfusion on clot firmness in thrombocytopenic patients with in vitro-performed fibrinogen concentrate substitution. MATERIALS AND METHODS: Thirty patients with haematological malignancy admitted for platelet transfusion were included. Haemostatic effects from platelet transfusion and ex vivo addition of fibrinogen concentrate at three different doses were evaluated by thromboelastometry, with clot firmness as the primary endpoint (A30 ExTEM assay). Secondary endpoints were other thromboelastometry parameters, thrombin generation parameters, activated partial thromboplastin time (APTT), prothrombin time PT, fibrinogen and factor XIII levels and a clinical bleeding score. RESULTS: Twenty patients (66%) had clinical bleeding signs by prior to transfusion. Platelets increased from 17 (range, 1-109) to 40 (range 2-139) × 10(9) L(-1) following transfusion, with a median corrected count increment of 16·7 (range, 0·8-43·5). The A30 value increased significantly by platelet transfusion from 35 ± 11 to 47 ± 10 mm, with no changes in thrombin generation. Fibrinogen concentrate dose-dependently increased A 30 (to 43 ± 10, 49 ± 9 and 50 ± 9 mm, respectively) and reduced parameters of thrombin generation at high doses. Platelet transfusion, together with fibrinogen concentrate, further increased clot firmness. APTT and PT were within normal range, whereas fibrinogen levels were slightly elevated. CONCLUSION: Fibrinogen concentrate increased clot firmness to the same degree as platelet transfusion in patients with low platelet count requiring platelet transfusion.

Learning endoscopic resection in the esophagus.

BACKGROUND: Endoscopic resection is the cornerstone of endoscopic management of esophageal early neoplasia. However, endoscopic resection is a complex technique requiring knowledge and expertise. Our aims were to identify the most important learning points in performing endoscopic resection in a training setting and to provide information on how to improve endoscopic resection technique. METHODS: Six gastroenterologists at centers with multidisciplinary expertise in upper gastrointestinal oncology participated in a structured endoscopic resection training program, consisting of four training days with lectures and hands-on training on live pigs, further one-to-one hands-on training days, and written feedback (by an expert) on videos of unsupervised endoscopic resection procedures. The first 20 endoscopic resections of each participant were prospectively registered. Ninety learning points were independently identified by participants using a standardized questionnaire and by an expert providing written feedback on 33 unsupervised endoscopic resection videos. Three expert endoscopists selected and ranked the most important learning points in a consensus meeting. Results. The top 10 tips (illustrated by unique videos of three perforations) were: (1) allow time for inspection and use a high-definition endoscope; (2) create a preprocedural plan by placing electrocoagulation markings; (3) know the management of bleeding; (4) optimize the endoscopic view by repeatedly cleaning out stomach and target area; (5) use a therapeutic endoscope during resection; (6) always perform a test suction; (7) keep instruments close to the tip; (8) lift edges in piecemeal endoscopic cap resections; (9) know the management of perforation; (10) pin specimens down. CONCLUSIONS: This study summarized the most important learning points for performing endoscopic resection encountered during a structured endoscopic resection training program.

Reactive oxygen species regulate Smac mimetic/TNFα-induced necroptotic signaling and cell death.

Necroptosis represents a key programmed cell death pathway involved in various physiological and pathophysiological conditions. However, the role of reactive oxygen species (ROS) in necroptotic signaling has remained unclear. In the present study, we identify ROS as critical regulators of BV6/tumor necrosis factor-α (TNFα)-induced necroptotic signaling and cell death. We show that BV6/TNFα-induced cell death depends on ROS production, as several ROS scavengers such as butylated hydroxyanisole, N-acetylcysteine, α-tocopherol and ethyl pyruvate significantly rescue cell death. Before cell death, BV6/TNFα-stimulated ROS generation promotes stabilization of the receptor-interacting protein kinase 1 (RIP1)/RIP3 necrosome complex via a potential positive feedback loop, as on the one hand radical scavengers attenuate RIP1/RIP3 necrosome assembly and phosphorylation of mixed lineage kinase domain like (MLKL), but on the other hand silencing of RIP1 or RIP3 reduces ROS production. Although MLKL knockdown effectively decreases BV6/TNFα-induced cell death, it does not affect RIP1/RIP3 interaction and only partly reduces ROS generation. Moreover, the deubiquitinase cylindromatosis (CYLD) promotes BV6/TNFα-induced ROS generation and necrosome assembly even in the presence of BV6, as CYLD silencing attenuates these events. Genetic silencing of phosphoglycerate mutase 5 or dynamin-related protein 1 (Drp1) fails to protect against BV6/TNFα-induced cell death. By demonstrating that ROS are involved in regulating BV6/TNFα-induced necroptotic signaling, our study provides new insights into redox regulation of necroptosis.

Impairment of antioxidant defense via glutathione depletion sensitizes acute lymphoblastic leukemia cells for Smac mimetic-induced cell death.

Evasion of apoptosis in pediatric acute lymphoblastic leukemia (ALL) is linked to aberrant expression of inhibitor of apoptosis (IAP) proteins and dysregulated redox homeostasis, rendering leukemic cells vulnerable to redox-targeting therapies. Here we discover that inhibition of antioxidant defenses via glutathione (GSH) depletion by buthionine sulfoximine (BSO) primes ALL cells for apoptosis induced by the Smac mimetic BV6 that antagonizes IAP proteins. Similarly, BSO cooperates with BV6 to induce cell death in patient-derived primary leukemic samples, underscoring the clinical relevance. In contrast, BSO does not sensitize non-malignant lymphohematopoietic cells from healthy donors toward BV6, pointing to some tumor selectivity. Mechanistically, both agents cooperate to stimulate reactive oxygen species (ROS) production, which is required for BSO/BV6-induced cell death, as ROS inhibitors (that is, N-acetylcysteine, MnTBAP, Trolox) significantly rescue cell death. Further, BSO and BV6 cooperate to trigger lipid peroxidation, which is necessary for cell death, as genetic or pharmacological blockage of lipid peroxidation by GSH peroxidase 4 (GPX4) overexpression or α-tocopherol significantly inhibits BSO/BV6-mediated cell death. Consistently, GPX4 knockdown or GPX4 inhibitor RSL3 enhances lipid peroxidation and cell death by BSO/BV6 cotreatment. The discovery of redox regulation of Smac mimetic-induced cell death has important implications for developing rational Smac mimetic-based combination therapies.

Investigation of border disease and bovine virus diarrhoea in sheep from 76 mixed cattle and sheep farms in eastern Switzerland.

The purpose of this study was to examine the occurrence of sheep persistently infected with Border disease virus (BDV) on 76 mixed cattle and sheep farms and whether seroconversion to BDV infection occurred in cattle of these farms. Seroprevalence of BDV and bovine viral disease virus (BVDV) infection in sheep was also investigated. Quantitative RT-PCR for pestivirus detection and an ELISA to detect pestivirus antibodies were used in 2'384 and 2'291 ovine blood samples, respectively. Another 27 seropositive sheep from ten flocks underwent serum neutralization testing to differentiate between BDV and BVDV antibodies. A BDV titre that was at least four times higher than the BVDV titre was interpreted as the result of BDV infection. Titres against BVDV were interpreted in an analogous fashion. All examined sheep were pestivirus-negative, 310 sheep were seropositive, 119 had an indeterminate titre and 1'862 were seronegative. The flock seroprevalence ranged from 0.0 to 73.9 %. Three of the 27 flocks that underwent serum neutralization testing were interpreted as BDV-infected because of 6 sheep with higher BDV titres, and 6 flocks were interpreted as BVDV-infected because of 14 sheep with higher BVDV titres.

Le but du présent travail était de savoir si, dans des exploitations détenant en parallèle des bovins et des moutons, on trouve des moutons infectés de façon persistante par la Border Disease (BD) et, dans ce cas, si les bovins de ces exploitations présentaient des anticorps contre la BVD. En outre on cherchait à connaître la séroprévalence des moutons quant aux anticorps BDV et BVDV. Les recherches ont été menées dans 76 exploitations détenant des moutons et des bovins. 2'384 échantillons sanguins de moutons ont été testés par PCR quantitative en temps réel quant aux pestivirus et 2'291 par ELISA quant aux anticorps contre les pestivirus. 27 autres échantillons, positifs à l'ELISA et provenant de 10 exploitations, ont été soumis à un test de séroneutralisation, afin de savoir si les anticorps étaient dirigés contre le BDV ou le BVDV. Chez les moutons dont le titre contre le BDV était au moins quatre fois plus élevé que celui contre le BVDV, on a considéré qu'il s'agissait d'une infection avec le BDV. Le titre BVDV a été évalué de la même manière. Tous les moutons testés quant aux pestivirus étaient virologiquement négatifs. Dans la recherche par ELISA, 310 échantillons étaient positifs, 119 douteux et 1'862 négatifs. La séroprévalence des exploitations variait entre 0.0 et 73.9 %. Lors de l'analyse par séroneutralisation des 27 échantillons positifs à l'ELISA, 6 échantillons provenant de 3 exploitations présentaient un titre BDV plus de quatre fois plus élevé que celui de BVDV. 14 échantillons provenant de 6 exploitations montraient des titres BVDV plus de quatre fois plus élevés que ceux de BDV. Sur la base de ces résultats, on doit admettre dans 3 exploitations une infection des moutons par BDV et dans 6 une infection par BVDV.

Predictive factors for initial treatment response after circumferential radiofrequency ablation for Barrett's esophagus with early neoplasia: a prospective multicenter study.

BACKGROUND AND STUDY AIMS: Radiofrequency ablation (RFA) is safe and effective for the eradication of neoplastic Barrett's esophagus; however, occasionally there is minimal regression after initial circumferential balloon-based RFA (c-RFA). This study aimed to identify predictive factors for a poor response 3 months after c-RFA, and to relate the percentage regression at 3 months to the final treatment outcome. METHODS: We included consecutive patients from 14 centers who underwent c-RFA for high grade dysplasia at worst. Patient and treatment characteristics were registered prospectively. "Poor initial response" was defined as < 50 % regression of the Barrett's esophagus 3 months after c-RFA, graded by two expert endoscopists using endoscopic images. Predictors of initial response were identified through logistic regression analysis. RESULTS: There were 278 patients included (median Barrett's segment C4M6). In poor initial responders (n = 36; 13 %), complete response for neoplasia (CR-neoplasia) was ultimately achieved in 86 % (vs. 98 % in good responders; P < 0.01) and complete response for intestinal metaplasia (CR-IM) in 66 % (vs. 95 %; P < 0.01). Poor responders required 13 months treatment (vs. 7 months; P < 0.01) for a median of four RFA sessions (vs. three; P < 0.01). We identified four independent baseline predictors of poor response: active reflux esophagitis (odds ratio [OR] 37.4; 95 % confidence interval [CI] 3.2 - 433.2); endoscopic resection scar regeneration with Barrett's epithelium (OR 4.7; 95 %CI 1.1 - 20.0); esophageal narrowing pre-RFA (OR 3.9; 95 %CI 1.0 - 15.1); and years of neoplasia pre-RFA (OR 1.2; 95 %CI 1.0 - 1.4). CONCLUSIONS: Patients with a poor initial response to c-RFA have a lower ultimate success rate for CR-neoplasia/CR-IM, require more treatment sessions, and a longer treatment period. A poor initial response to c-RFA occurs more frequently in patients who regenerate their endoscopic resection scar with Barrett's epithelium, and those with ongoing reflux esophagitis, neoplasia in Barrett's esophagus for a longer time, or a narrow esophagus.

Optimization of the reconstruction interval in neurovascular 4D-CTA imaging. A technical note.

Time resolved whole brain CT angiography (4D-CTA) is a novel imaging technology providing information regarding blood flow. One of the factors that influence the diagnostic value of this examination is the temporal resolution, which is affected by the gantry rotation speed during acquisition and the reconstruction interval during post-processing. Post-processing determines the time spacing between two reconstructed volumes and, unlike rotation speed, does not affect radiation burden. The data sets of six patients who underwent a cranial 4D-CTA were used for this study. Raw data was acquired using a 320-slice scanner with a rotation speed of 2 Hz. The arterial to venous passage of an intravenous contrast bolus was captured during a 15 s continuous scan. The raw data was reconstructed using four different reconstruction-intervals: 0.2, 0.3, 0.5 and 1.0 s. The results were rated by two observers using a standardized score sheet. The appearance of each lesion was rated correctly in all readings. Scoring for quality of temporal resolution revealed a stepwise improvement from the 1.0 s interval to the 0.3 s interval, while no discernable improvement was noted between the 0.3 s and 0.2 s interval. An increase in temporal resolution may improve the diagnostic quality of cranial 4D-CTA. Using a rotation speed of 0.5 s, the optimal reconstruction interval appears to be 0.3 s, beyond which, changes can no longer be discerned.

Learning to perform endoscopic resection of esophageal neoplasia is associated with significant complications even within a structured training program.

BACKGROUND AND STUDY AIMS: Endoscopic resection is the cornerstone of endoscopic treatment of esophageal high grade dysplasia or early cancer. Endoscopic resection is, however, a technically demanding procedure, which requires training and expertise. The aim of the current study was to prospectively evaluate efficacy and safety of the first 120 endoscopic resection procedures of early esophageal neoplasia performed by six endoscopists (20 endoscopic resections each) who were participating in an endoscopic resection training program. PATIENTS AND METHODS: The program consisted of four tri-monthly 1-day courses with lectures, live-demonstrations, hands-on training on anesthetized pigs, and one-on-one hands-on training days. Gastroenterologists from centers with multidisciplinary expertise in upper gastrointestinal oncology participated, together with an endoscopy nurse and a pathologist. Outcome measures were complete endoscopic removal of the target area and acute complications. RESULTS: A total of 120 consecutive esophageal endoscopic resection procedures (85 ER-cap, 35 multiband mucosectomy [MBM]) were performed by six endoscopists: 109 in Barrett's esophagus, 11 for squamous neoplasia; 85 piecemeal endoscopic resections (median 3 specimens, interquartile range 2 - 4 specimens). Complete endoscopic removal was achieved in 111 /120 cases (92.5 %). Six perforations occurred (5.0 %): five were effectively treated endoscopically (clips, covered stent), and one patient underwent esophagectomy. There were 11 acute mild bleedings (9.2 %), which were managed endoscopically. Perforations occurred in ER-cap procedures performed by four participants (7.1 % ER-cap vs. 0 % MBM; P = 0.18), and in 1.7 % of the first 10 endoscopic resections and 8.3 % of the second 10 endoscopic resections per endoscopist (P = 0.26). CONCLUSION: In this intense, structured training program, the first 120 esophageal endoscopic resections performed by six participants were associated with a 5.0 % perforation rate. Although perforations were adequately managed, performing 20 endoscopic resections may not be sufficient to reach the peak of the learning curve in endoscopic resection.