Development and external validation of a model to predict complex treatment after RFA for Barrett's esophagus with early neoplasia

Background & Aims: Endoscopic eradication therapy for Barrett's esophagus (BE)-related neoplasia is safe and leads to complete eradication in the majority of patients. However, a subgroup will experience a more complex treatment course with a risk for failure or disease progression. Early identification of these patients may improve patient counseling and treatment outcomes. We aimed to develop a prognostic model for a complex treatment course. Methods: We collected data from a nationwide registry that captures outcomes for all patients undergoing endoscopic eradication therapy for early BE neoplasia. A complex treatment course was defined as neoplastic progression, treatment failure, or the need for endoscopic resection during the radiofrequency ablation treatment phase. We developed a prognostic model using logistic regression. We externally validated our model in an independent registry. Results: A total of 1386 patients were included, of whom 78 (6%) had a complex treatment course. Our model identified patients with a BE length of 9 cm or longer with a visible lesion containing high-grade dysplasia/cancer, and patients with less than 50% squamous conversion after radiofrequency ablation were identified as high risk for a complex treatment. This applied to 8% of the study population and included 93% of all treatment failures and 76% of all patients with advanced neoplastic progression. The model appeared robust in multiple sensitivity analyses and performed well in external validation (area under the curve, 0.84). Conclusions: We developed a prognostic model that identified patients with a BE length of 9 cm or longer and high-grade dysplasia/esophageal adenocarcinoma and those with poor squamous regeneration as high risk for a complex treatment course. The good performance in external validation suggests that it may be used in clinical management (Netherlands Trial Register: NL7039)

The association between antihypertensive drugs and glioma

We pursued an association between hypertension and gliomas by investigating whether antihypertensive drugs (AHD) are associated with an increased glioma risk by a population-based nested case–control study using the PHARMO database; this links dispensing records of prescription drugs to hospital discharge data on an individual basis. Pathological data were derived from the Dutch nationwide registry of histo- and cytopathology. A total of 306 glioma cases incident between 1997 and 2003 were matched to 1108 controls for year of birth, sex, geographical region and duration of follow-up. Exposure was defined as cumulative duration of AHD use and, in an alternative analysis, as cumulative dose. We estimated the magnitude of the association with conditional logistic regression analysis. Cumulative use of any AHD for more than 6 months was associated with an increased risk of glioma (OR 1.45; 95% CI 1.03–2.04). After stratification for different groups of AHD, no significantly increased risk of glioma was found for any class of AHD. After excluding a latency period of 3 years before the date of diagnosis, no association was found. In conclusion, the use of AHD seems to be associated with an increased risk of glioma, but this is probably not causal

Associations of Arterial Stiffness With Cognitive Performance, and the Role of Microvascular Dysfunction:The Maastricht Study

The mechanisms underlying cognitive impairment are incompletely understood but may include arterial stiffness and microvascular dysfunction. In the population-based Maastricht Study, we investigated the association between arterial stiffness and cognitive performance, and whether any such association was mediated by microvascular dysfunction. We included cross-sectional data of 2544 participants (age, 59.7 years; 51.0% men; 26.0% type 2 diabetes mellitus). We used carotid-femoral pulse wave velocity and carotid distensibility coefficient as measures of aortic and carotid stiffness, respectively. We calculated a composite score of microvascular dysfunction based on magnetic resonance imaging features of cerebral small vessel disease, flicker light-induced retinal arteriolar and venular dilation response, albuminuria, and plasma biomarkers of microvascular dysfunction (sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [von Willebrand factor]). Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the average of these domains. Higher aortic stiffness (per m/s) was associated with lower cognitive function (β, -0.018 SD [95% CI, -0.036 to -0.000]) independent of age, sex, education, and cardiovascular risk factors, but higher carotid stiffness was not. Higher aortic stiffness (per m/s) was associated with a higher microvascular dysfunction score (β, 0.034 SD [95% CI, 0.014 to 0.053]), and a higher microvascular dysfunction score (per SD) was associated with lower cognitive function (β, -0.089 SD [95% CI, -0.124 to -0.053]). Microvascular dysfunction significantly explained 16.2% of the total effect of aortic stiffness on cognitive function. The present study showed that aortic stiffness, but not carotid stiffness, is independently associated with worse cognitive performance, and that this association is in part explained by microvascular dysfunction

Dysplastic Recurrence After Successful Treatment for Early Barrett's Neoplasia:Development and Validation of a Prediction Model

Background & Aims: The combination of endoscopic resection and radiofrequency ablation is the treatment of choice for eradication of Barrett's esophagus (BE) with dysplasia and/or early cancer. Currently, there are no evidence-based recommendations on how to survey patients after successful treatment, and most patients undergo frequent follow-up endoscopies. We aimed to develop and externally validate a prediction model for visible dysplastic recurrence, which can be used to personalize surveillance after treatment. Methods: We collected data from the Dutch Barrett Expert Center Registry, a nationwide registry that captures outcomes from all patients with BE undergoing endoscopic treatment in the Netherlands in a centralized care setting. We used predictors related to demographics, severity of reflux, histologic status at baseline, and treatment characteristics. We built a Fine and Gray survival model with least absolute shrinkage and selection operator penalization to predict the incidence of visible dysplastic recurrence after initial successful treatment. The model was validated externally in patients with BE treated in Switzerland and Belgium. Results: A total of 1154 patients with complete BE eradication were included for model building. During a mean endoscopic follow-up of 4 years, 38 patients developed recurrent disease (1.0%/person-year). The following characteristics were independently associated with recurrence (strongest to weakest predictor): a new visible lesion during treatment phase, higher number of endoscopic resection treatments, male sex, increasing BE length, high-grade dysplasia or cancer at baseline, and younger age. External validation showed a C-statistic of 0.91 (95% confidence interval, 0.86–0.94) with good calibration. Conclusions: This is the first externally validated model to predict visible dysplastic recurrence after successful endoscopic eradication treatment of BE with dysplasia or early cancer. On external validation, our model has good discrimination and calibration. This model can help clinicians and patients to determine a personalized follow-up strategy

Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal.

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient

Incidence and outcomes of poor healing and poor squamous regeneration after radiofrequency ablation therapy for early Barrett's neoplasia

BACKGROUND: Although endoscopic eradication therapy with radiofrequency ablation (RFA) is effective in most Barrett's Esophagus (BE) patients, some might experience poor healing (PH) and/or poor squamous regeneration (PSR). We aimed to evaluate PH/PSR incidence and treatment outcomes. METHODS: We included all patients treated with RFA for early BE neoplasia, from a nationwide Dutch registry based on a joint treatment protocol. PH was defined as active inflammatory changes or visible ulcerations ≥3 months post-RFA, PSR as <50% squamous regeneration, and treatment success as complete eradication of BE (CE-BE). Results 1,386 patients (median BE C2M5) underwent RFA with baseline low-grade dysplasia (27%), high-grade dysplasia (30%), or early cancer (43%). In all 134 patients with PH (10%), additional time and acid suppression resulted in complete esophageal healing. 67/134 (50%) had normal regeneration with 97% CE-BE. In total, 74 patients had PSR (5%). As compared to patients with normal squamous regeneration, PSR patients had a higher risk for treatment failure (64% versus 2%, RR 27 [95% CI 18-40]) and progression to advanced disease (15% versus <1%, RR 30 [95% CI 12-81]). Higher BMI, longer BE, reflux esophagitis, and <50% squamous regeneration after baseline endoscopic resection were independently associated with PSR in multivariable logistic regression. Conclusions In half of the patients with PH, additional time and acid suppression may lead to normal squamous regeneration and excellent treatment outcomes. However, if patients experience PSR, the risk for treatment failure and progression to advanced disease is significantly increased with a relative risk of 27 and 30, respectively

Analysis of metastases rates during follow-up after endoscopic resection of early "high-risk" esophageal adenocarcinoma

BACKGROUND AND AIMS: After endoscopic resection (ER) of early esophageal adenocarcinoma (EAC), the optimal management of patients with high-risk histological features for lymph node metastases (LNM) (i.e., submucosal invasion, poor differentiation grade, or lymphovascular invasion (LVI)), remains unclear. We aimed to evaluate outcomes of endoscopic follow-up after ER for high-risk EAC. METHODS: For this retrospective cohort study, data was collected from all Dutch patients managed with endoscopic follow-up (endoscopy, endoscopic ultrasound) after ER for high-risk EAC between 2008 and 2019. We distinguished 3 groups: intramucosal cancers with high-risk features, submucosal cancers with low-risk features, and submucosal cancers with high-risk features. Primary outcome was the annual risk for metastases during follow-up, stratified for baseline histology. RESULTS: A total of 120 patients met the selection criteria. Median FU was 29 months (IQR 15-48). Metastases were observed in 5/25 (annual risk 6.9%; 95% CI 3.0-15), 1/55 (annual risk 0.7%; 95% CI 0-4.0) and 3/40 (annual risk 3.0%; 95% CI 0-7.0) in high-risk intramucosal, low-risk submucosal, and high-risk submucosal cancers, respectively. CONCLUSIONS: Whereas the annual metastasis rate for high-risk submucosal EAC (3.0%) was somewhat lower than expected in comparison with previous reported percentages, the annual metastasis rate of 6.9% for high-risk intramucosal EAC is new and worrisome. This calls for further prospective studies and suggests that strict follow-up of this small subgroup is warranted until prospective data are available

Measurement of the B0_s semileptonic branching ratio to an orbitally excited D_s** state, Br(B0_s -> Ds1(2536) mu nu)

In a data sample of approximately 1.3 fb-1 collected with the D0 detector between 2002 and 2006, the orbitally excited charm state D_s1(2536) has been observed with a measured mass of 2535.7 +/- 0.6 (stat) +/- 0.5 (syst) MeV via the decay mode B0_s -> D_s1(2536) mu nu X. A first measurement is made of the branching ratio product Br(b(bar) -> D_s1(2536) mu nu X).Br(D_s1(2536)->D* K0_S). Assuming that D_s1(2536) production in semileptonic decay is entirely from B0_s, an extraction of the semileptonic branching ratio Br(B0_s -> D_s1(2536) mu nu X) is made.Comment: 7 pages, 2 figures, LaTeX, version with minor changes as accepted by Phys. Rev. Let

Measurement of the t-channel single top quark production cross section

The D0 collaboration reports direct evidence for electroweak production of single top quarks through the t-channel exchange of a virtual W boson. This is the first analysis to isolate an individual single top quark production channel. We select events containing an isolated electron or muon, missing transverse energy, and two, three or four jets from 2.3 fb^-1 of ppbar collisions at the Fermilab Tevatron Collider. One or two of the jets are identified as containing a b hadron. We combine three multivariate techniques optimized for the t-channel process to measure the t- and s-channel cross sections simultaneously. We measure cross sections of 3.14 +0.94 -0.80 pb for the t-channel and 1.05 +-0.81 pb for the s-channel. The measured t-channel result is found to have a significance of 4.8 standard deviations and is consistent with the standard model prediction.Comment: 7 pages, 6 figure

Simultaneous measurement of the ratio B(t->Wb)/B(t->Wq) and the top quark pair production cross section with the D0 detector at sqrt(s)=1.96 TeV

We present the first simultaneous measurement of the ratio of branching fractions, R=B(t->Wb)/B(t->Wq), with q being a d, s, or b quark, and the top quark pair production cross section sigma_ttbar in the lepton plus jets channel using 0.9 fb-1 of ppbar collision data at sqrt(s)=1.96 TeV collected with the D0 detector. We extract R and sigma_ttbar by analyzing samples of events with 0, 1 and >= 2 identified b jets. We measure R = 0.97 +0.09-0.08 (stat+syst) and sigma_ttbar = 8.18 +0.90-0.84 (stat+syst)} +/-0.50 (lumi) pb, in agreement with the standard model prediction.Comment: submitted to Phys.Rev.Letter