Molecular pathology is becoming more and more important in present day pathology. A major challenge for any molecular test is its ability to reliably detect mutations in samples consisting of ...mixtures of tumor cells and normal cells, especially when the tumor content is low. The minimum percentage of tumor cells required to detect genetic abnormalities is a major variable. Information on tumor cell percentage is essential for a correct interpretation of the result. In daily practice, the percentage of tumor cells is estimated by pathologists on hematoxylin and eosin (H&E)-stained slides, the reliability of which has been questioned. This study aimed to determine the reliability of estimated tumor cell percentages in tissue samples by pathologists. On 47 H&E-stained slides of lung tumors a tumor area was marked. The percentage of tumor cells within this area was estimated independently by nine pathologists, using categories of 0–5%, 6–10%, 11–20%, 21–30%, and so on, until 91–100%. As gold standard, the percentage of tumor cells was counted manually. On average, the range between the lowest and the highest estimate per sample was 6.3 categories. In 33% of estimates, the deviation from the gold standard was at least three categories. The mean absolute deviation was 2.0 categories (range between observers 1.5–3.1 categories). There was a significant difference between the observers (P<0.001). If 20% of tumor cells were considered the lower limit to detect a mutation, samples with an insufficient tumor cell percentage (<20%) would have been estimated to contain enough tumor cells in 27/72 (38%) observations, possibly causing false negative results. In conclusion, estimates of tumor cell percentages on H&E-stained slides are not accurate, which could result in misinterpretation of test results. Reliability could possibly be improved by using a training set with feedback.
In a previous study, we detected a significant association between phosphoserine aminotransferase 1 (PSAT1) hyper-methylation and mRNA levels to outcome to tamoxifen treatment in recurrent disease. ...We here aimed to study the association of PSAT1 protein levels to outcome upon tamoxifen treatment and to obtain more insight in its role in tamoxifen resistance. A cohort of ER positive, hormonal therapy naïve primary breast carcinomas was immunohistochemically (IHC) stained for PSAT1. Staining was analyzed for association with patient's time to progression (TTP) and overall response on first-line tamoxifen for recurrent disease. PSAT1 mRNA levels were also assessed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR; n = 161) and Affymetrix GeneChip (n = 155). Association of PSAT1 to biological pathways on tamoxifen outcome were assessed by global test. PSAT1 protein and mRNA levels were significantly associated to poor outcome to tamoxifen treatment. When comparing PSAT1 protein and mRNA levels, IHC and RT-qPCR data showed a significant association. Global test results showed that cytokine and JAK-STAT signaling were associated to PSAT1 expression. We hereby report that PSAT1 protein and mRNA levels measured in ER positive primary tumors are associated with poor clinical outcome to tamoxifen.
The aim of this study was to investigate the efficacy and safety of the hybrid ultrathin-strut sirolimus-eluting stent (SES) with biodegradable polymer compared with the thin-strut everolimus-eluting ...stent (EES) with durable polymer in successfully recanalized chronic total occlusions (CTOs).
The introduction of drug-eluting stents revolutionized the treatment of CTOs. However, limited data are available on new-generation drug-eluting stents with biodegradable polymer in CTOs.
In this multicenter trial, patients were randomized, after successful CTO recanalization, to either SES or EES. The primary noninferiority endpoint was in-segment late lumen loss (noninferiority margin 0.2 mm). Secondary endpoints included in-stent late lumen loss and clinical endpoints.
Overall, 330 patients were included. At 9 months, angiography was available in 281 patients (85%). Duration of occlusion ≥3 months was 92.5%, with mean stent length of 52.4 ± 28.1 mm versus 52.3 ± 26.5 mm in the SES and EES groups. The primary noninferiority endpoint, in-segment late lumen loss, was not met for SES versus EES (0.13 ± 0.63 mm vs. 0.02 ± 0.47 mm; p = 0.08, 2-sided; difference 0.11 mm; 95% confidence interval: -0.01 to 0.25 mm; p
= 0.11, 1-sided). In-stent late lumen loss was comparable between SES and EES (0.12 ± 0.59 mm vs. 0.07 ± 0.46 mm; p = 0.52). The incidence of in-stent and in-segment binary restenosis was significantly higher with SES compared with EES (8.0% vs. 2.1%; p = 0.028), with comparable rates of reocclusions (2.2% vs. 1.4%; p = 0.68). Clinically indicated target lesion and target vessel revascularization (9.2% vs. 4.0% p = 0.08 and 9.2% vs. 6.0% p = 0.33), target vessel failure (9.9% vs. 6.6%; p = 0.35), and definite or probable stent thrombosis (0.7% vs. 0.7%; p = 1.00) were comparable between the SES and EES groups.
This randomized trial failed to show noninferiority of hybrid SES relative to EES in terms of in-segment late lumen loss in successfully recanalized CTOs. Furthermore, a statistically significantly higher rate of binary restenosis was found with SES.
The northwest European heathland landscape with its characteristic communities of nutrient-poor and acidic soils has a high nature value, because of its locally high biodiversity and the distinct ...site conditions. In order to conserve and restore the heathlands, numerous rehabilitation projects have been performed, although with varying success. This is partly due to the fact that the key biogeochemical processes distinguishing the various vegetation types within the heathlands are not known in detail.
Therefore, we performed a statistical survey on the main communities and their soil characteristics. In addition, we analyzed the data for key factors determining biodiversity in the heathland landscape.
Data from previous studies and surveys was used to compile a dataset of 267 vegetation relevés (classified as EUNIS habitat types) with extensive soil measurements (22 parameters). A canonical discriminant analysis revealed that soil acidity explained most of the differences between the habitat types, while soil moisture content and soil fertility were less important. Acidity-related factors as Al
3+, Al/Ca-ratio and pH were also strongly correlated to plant diversity in the majority of the habitat types, respectively, the species-rich
Nardus grasslands, the Rhynchosporion communities and the species-rich
Molinia meadows. In the dry heaths and over the total heathland landscape, plant diversity was negatively correlated with soil
NH
4
+
-concentrations. Only in wet heath, nutrient availability, in this case P, was the primary factor in explaining plant diversity.
This study presents ranges for all major soil parameters for the studied well-developed heathland habitat types, thereby providing clear guidelines for conservation and restoration.
Abstract Objective To describe trends in the use of epidural analgesia (EA) and to evaluate the association of EA with operative deliveries. Study design In this population-based, retrospective ...cohort study, women with an intention to deliver vaginally of a term, cephalic, singleton between 2000 and 2009 ( n = 1378 458) were included. Main outcome measures were labor EA rates, unplanned caesarean section (CS), and instrumental vaginal delivery (IVD) including deliveries by either vacuum or forceps. Data were obtained from the Perinatal Registry of The Netherlands and logistic regression analyses were used. Results Among nulliparous, EA use almost tripled over the 10-year span (from 7.7% to 21.9%), while rates of CS and IVD did not change much (+2.8% and −3.3%, respectively). Among multiparous, EA use increased from 2.4% to 6.8%, while rates of CS and IVD changed slightly (+0.8% and −0.7%, respectively). Multivariable analysis showed a positive association of EA with CS, which weakened in ten years, from an adjusted OR of 2.35 (95% CI, 2.18 to 2.54) to 1.69 (95% CI, 1.60 to 1.79; p < 0.001) in nulliparous, and from an adjusted OR of 3.17 (95% CI, 2.79 to 3.61) to 2.56 (95% CI, 2.34 to 2.81; p < 0.001) in multiparous women. A weak inverse association between EA and IVD was found among nulliparous (adjusted OR, 0.76; 95% CI, 0.75 to 0.78), and a positive one among multiparous women (adjusted OR, 2.08; 95% CI, 2.00 to 2.16). Both associations grew slightly weaker over time. Conclusions A near triplication of EA use in The Netherlands in ten years was accompanied by relatively stable rates of operative deliveries. The association between EA and operative delivery became weaker. This supports the idea that EA is not an important causal factor of operative deliveries.
The frequency of summer flood events has strongly increased in Eastern Europe during the last decades. The creation of water storage areas to avoid flooding is often combined with the re-creation of ...more natural and biodiverse riverine systems. This urges the need to understand the consequences of summer inundation, when microbial activity is significantly higher than during winter inundation, for floodplain biogeochemistry. In order to test the interacting effects of temporal flooding, water quality and agricultural use we used a mesocosm design with sods including vegetation from an area along a tributary of the Vistula River, where water storage compartments have been planned. Concentrations of nitrate and sulphate in the flood water, expected to interfere with soil redox processes, were varied at environmentally relevant concentrations. Inundation led to increased nutrient mobilization in all treatments, particularly for phosphate which reached very high concentrations in both soil water (200-300 μmol l⁻¹) and overlaying surface water (25-35 μmol l⁻¹) as a result of iron reduction. The response was clearly linked to different soil characteristics like the Olsen P concentration, probably caused by varying kind of land use. Unexpectedly, the flood water quality played a less important role in the response to short-term flooding. This could partly be explained by the relatively low infiltration rate into these waterlogged soils, indicating the importance of local hydrology. The findings of this study are important to understand and predict the effects of (more frequent) summer flooding of Eastern European rivers. It also indicates that it is necessary to take into account the soil quality in assessing the consequences of planned measures on biodiversity and ecosystem functioning.
Discussing the individual probability of a successful vaginal birth after caesarean (VBAC) can support decision making. The aim of this study is to externally validate a prediction model for the ...probability of a VBAC in a Dutch population.
In this prospective cohort study in 12 Dutch hospitals, 586 women intending VBAC were included. Inclusion criteria were singleton pregnancies with a cephalic foetal presentation, delivery after 37 weeks and one previous caesarean section (CS) and preference for intending VBAC. The studied prediction model included six predictors: pre-pregnancy body mass index, previous vaginal delivery, previous CS because of non-progressive labour, Caucasian ethnicity, induction of current labour, and estimated foetal weight ≥90th percentile. The discriminative and predictive performance of the model was assessed using receiver operating characteristic curve analysis and calibration plots.
The area under the curve was 0.73 (CI 0.69-0.78). The average predicted probability of a VBAC according to the prediction model was 70.3% (range 33-92%). The actual VBAC rate was 71.7%. The calibration plot shows some overestimation for low probabilities of VBAC and an underestimation of high probabilities.
The prediction model showed good performance and was externally validated in a Dutch population. Hence it can be implemented as part of counselling for mode of delivery in women choosing between intended VBAC or planned CS after previous CS.
AbstractBackgroundThe advent of bioresorbable vascular scaffolds (BVS) was considered as a potential improvement in percutaneous coronary intervention (PCI) after the groundbreaking development of ...drug eluting stents (DES). However, the clinical performance, long-term safety and efficacy of BVS in complex coronary lesions remain uncertain. COMPARE ABSORB, a multicenter, single blind, prospective randomized trial, aims to compare the clinical outcomes between the Absorb BVS and Xience everolimus-eluting metallic stent (EES) in patients with coronary artery disease and a high risk of restenosis. DesignCOMPARE ABSORB is designed to enroll 2100 patients at up to 45 European sites. Enrolled patients will possess high risk for restenosis due to clinical profile or coronary lesion complexity and will undergo elective or emergent PCI. Once included in the study, patients will receive either Absorb BVS or Xience EES. Specific advice on implantation technique including mandatory pre-dilatation, sizing and post-dilatation (PSP), will be used in the Absorb BVS arm. The primary endpoint is target lesion failure (TLF), a device-oriented composite endpoint (cardiac death, target vessel myocardial infarction and clinically-indicated target lesion revascularization). The trial is powered to assess non-inferiority of Absorb BVS compared with Xience EES with a predetermined non-inferiority margin of 4.5% at 1 year after index procedure. The clinical follow-up will continue for 7 years. ConclusionsThe prospective COMPARE ABSORB randomized trial ( ClinicalTrials.govNCT02486068) will help to assess the long-term safety and efficacy of Absorb BVS compared with Xience EES in the treatments of patients with complex coronary artery disease and a high attendant risk of restenosis.
Abstract Prelabor rupture of membranes (PROM) is a common obstetrical problem, but its diagnosis is frequently problematic. Lacking a gold standard, the diagnosis is equivocal in some 10% of cases. ...We performed a systematic review to assess the accuracy of several tests for the diagnosis of PROM in these equivocal cases. We performed an electronic search in PubMed, Embase, DARE and the Cochrane Library and reference lists for potentially missed articles. No language restrictions were used. Only accuracy studies for diagnostic methods for PROM in women with equivocal PROM were selected. The studies were scored according to STARD and QUADAS guidelines. Based on the full description of reference and index tests, an expert panel finally decided whether the selected articles were of sufficient quality to be included. We identified 3864 studies of which 146 full manuscripts were obtained. We excluded 133 due to multiple reasons. The remaining 13 studies were scored by an expert panel. Only three articles with a total of 155 patients fulfilled all criteria. These articles tested three different methods, pH measurement (64 patients), insulin-like growth factor binding protein-1 (ILGBP-1, 83 patients) and alpha fetoprotein (AFP, 8 patients). Sensitivity varied from 88% (pH) to 100% (AFP), specificity varied from 56% (ILGPP-1) to 100% (AFP). Based on the limited evidence on the accuracy of tests to diagnose ruptured membranes, we conclude that the use of a particular test cannot be recommended.
Most studies on birth settings investigate the association between planned place of birth at the start of labor and birth outcomes and intervention rates. To optimize maternity care it also is ...important to pay attention to the entire process of pregnancy and childbirth. This study explores the association between the initial preferred place of birth and model of care, and the course of pregnancy and labor in low-risk nulliparous women in the Netherlands.
As part of a Dutch prospective cohort study (2007-2011), we compared medical indications during pregnancy and birth outcomes of 576 women who initially preferred a home birth (n = 226), a midwife-led hospital birth (n = 168) or an obstetrician-led hospital birth (n = 182). Data were obtained by a questionnaire before 20 weeks of gestation and by medical records. Analyses were performed according to the initial preferred place of birth.
Low-risk nulliparous women who preferred a home birth with midwife-led care were less likely to be diagnosed with a medical indication during pregnancy compared to women who preferred a birth with obstetrician-led care (OR 0.41 95% CI 0.25-0.66). Preferring a birth with midwife-led care - both at home and in hospital - was associated with lower odds of induced labor (OR 0.51 95% CI 0.28-0.95 respectively OR 0.42 95% CI 0.21-0.85) and epidural analgesia (OR 0.32 95% CI 0.18-0.56 respectively OR 0.34 95% CI 0.19-0.62) compared to preferring a birth with obstetrician-led care. In addition, women who preferred a home birth were less likely to experience augmentation of labor (OR 0.54 95% CI 0.32-0.93) and narcotic analgesia (OR 0.41 95% CI 0.21-0.79) compared to women who preferred a birth with obstetrician-led care. We observed no significant association between preferred place of birth and mode of birth.
Nulliparous women who initially preferred a home birth were less likely to be diagnosed with a medical indication during pregnancy. Women who initially preferred a birth with midwife-led care - both at home and in hospital - experienced lower rates of interventions during labor. Although some differences can be attributed to the model of care, we suggest that characteristics and attitudes of women themselves also play an important role.
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