Novel biomarkers for the prediction of metastasis in colorectal cancer

INTRODUCTION In patients with metastatic colorectal cancers, multimodal management and the use of biological agents such as monoclonal antibodies have had major positive effects on survival. The ability to predict which patients may be at 'high risk' of distant metastasis could have major implications on patient management. Histomorphological, immunohistochemical or molecular biomarkers are currently being investigated in order to test their potential value as predictors of metastasis. AREAS COVERED Here, the author reviews the clinical and functional data supporting the investigation of three novel promising biomarkers for the prediction of metastasis in patients with colorectal cancer: tumor budding, Raf1 kinase inhibitor protein (RKIP) and metastasis-associated in colon cancer-1 (MACC1). EXPERT OPINION The lifespan of most potential biomarkers is short as evidenced by the rare cases that have successfully made their way into daily practice such as KRAS or microsatellite instability (MSI) status. Although the three biomarkers reviewed herein have the potential to become important predictive biomarkers of metastasis, they have similar hurdles to overcome before they can be implemented into clinical management: standardization and validation in prospective patient cohorts.

Variability between laboratories performing coagulation tests with identical platforms: a nationwide evaluation study.

BACKGROUND While the assessment of analytical precision within medical laboratories has received much attention in scientific enquiry, the degree of as well as the sources causing variation between them remains incompletely understood. In this study, we quantified the variance components when performing coagulation tests with identical analytical platforms in different laboratories and computed intraclass correlations coefficients (ICC) for each coagulation test. METHODS Data from eight laboratories measuring fibrinogen twice in twenty healthy subjects with one out of 3 different platforms and single measurements of prothrombin time (PT), and coagulation factors II, V, VII, VIII, IX, X, XI and XIII were analysed. By platform, the variance components of (i) the subjects, (ii) the laboratory and the technician and (iii) the total variance were obtained for fibrinogen as well as (i) and (iii) for the remaining factors using ANOVA. RESULTS The variability for fibrinogen measurements within a laboratory ranged from 0.02 to 0.04, the variability between laboratories ranged from 0.006 to 0.097. The ICC for fibrinogen ranged from 0.37 to 0.66 and from 0.19 to 0.80 for PT between the platforms. For the remaining factors the ICC's ranged from 0.04 (FII) to 0.93 (FVIII). CONCLUSIONS Variance components that could be attributed to technicians or laboratory procedures were substantial, led to disappointingly low intraclass correlation coefficients for several factors and were pronounced for some of the platforms. Our findings call for sustained efforts to raise the level of standardization of structures and procedures involved in the quantification of coagulation factors.

The Swiss Schools have been Governed by Local Lay Authorities

After the introduction of the liberal-democratic constitutions in the Swiss cantons in the first half of the 1830ies the grid of existing schools has been systemized and broadly expanded. The school systems have ever since been characterized by one key element: a special local authority type called „Schulkommission“ or „Schulpflege“. They take the form of committees consisting of laymen that are appointed by democratic elections like all the other executive bodies on the different federal levels in Switzerland. When it comes to their obligations and activities these community level school committees conform very much to the school boards in the American and Canadian school systems. They are accountable for the selection and supervision of the teachers. They approve decisions about the school careers of pupils and about curricular matters like the choice of school books. Normally their members are elected by the local voters for four year terms of office (reelection remains possible) and with regard to pedagogics they normally are non-professionals. The board members are responsible for classes and teachers assigned to them and they have to go to see them periodically. These visitations and the board meetings each month together with the teachers enable the board members to attain a deep insight into what happens in their schools over the course of their term of office. But they are confronted as laymen with a professional teaching staff and with educational experts in the public administration. Nevertheless this form of executive power by non-professionals is constitutive for the state governance in the Swiss as well as in other national political environments. It corresponds to the principles of subsidiarity and militia and therefore allows for a strong accentuation of liberty and the right of self-determination, two axioms at the very base of democratic federalist ideology. This governance architecture with this strong accent on local anchorage features substantial advantages for the legitimacy and acceptability of political and administrative decisions. And this is relevant especially in the educational area because the rearing of the offspring is a project of hope and, besides, quite costly. In the public opinion such supervision bodies staffed by laymen seem to have certain credibility advances in comparison with the professional administration. They are given credit to be capable of impeding the waste of common financial resources and of warranting the protection and the fostering of the community’s children at once. Especially because of their non-professional character they are trusted to be reliably immune against organizational blindness and they seem to be able to defend the interests of the local community against the standardization and centralization aspirations originating from the administrational expertocracy. In the paper these common rationales will be underpinned by results of a comprehensive historical analysis of the Session protocols of three Bernese school commissions from 1835 to 2005.

Precipitation over the past four centuries in the Dieshan Mountains as inferred from tree rings: An introduction to an HHT-based method

To improve our understanding of the Asian monsoon system, we developed a hydroclimate reconstruction in a marginal monsoon shoulder region for the period prior to the industrial era. Here, we present the first moisture sensitive tree-ring chronology, spanning 501 years for the Dieshan Mountain area, a boundary region of the Asian summer monsoon in the northeastern Tibetan Plateau. This reconstruction was derived from 101 cores of 68 old-growth Chinese pine (Pinus tabulaeformis) trees. We introduce a Hilbert–Huang Transform (HHT) based standardization method to develop the tree-ring chronology, which has the advantages of excluding non-climatic disturbances in individual tree-ring series. Based on the reliable portion of the chronology, we reconstructed the annual (prior July to current June) precipitation history since 1637 for the Dieshan Mountain area and were able to explain 41.3% of the variance. The extremely dry years in this reconstruction were also found in historical documents and are also associated with El Niño episodes. Dry periods were reconstructed for 1718–1725, 1766–1770 and 1920–1933, whereas 1782–1788 and 1979–1985 were wet periods. The spatial signatures of these events were supported by data from other marginal regions of the Asian summer monsoon. Over the past four centuries, out-of-phase relationships between hydroclimate variations in the Dieshan Mountain area and far western Mongolia were observed during the 1718–1725 and 1766–1770 dry periods and the 1979–1985 wet period.

Managing Things and Services with Semantics: A Survey

This paper presents a survey on the usage, opportunities and pitfalls of semantic technologies in the Internet of Things. The survey was conducted in the context of a semantic enterprise integration platform. In total we surveyed sixty-one individuals from industry and academia on their views and current usage of IoT technologies in general, and semantic technologies in particular. Our semantic enterprise integration platform aims for interoperability at a service level, as well as at a protocol level. Therefore, also questions regarding the use of application layer protocols, network layer protocols and management protocols were integrated into the survey. The survey suggests that there is still a lot of heterogeneity in IoT technologies, but first indications of the use of standardized protocols exist. Semantic technologies are being recognized as of potential use, mainly in the management of things and services. Nonetheless, the participants still see many obstacles which hinder the widespread use of semantic technologies: Firstly, a lack of training as traditional embedded programmers are not well aware of semantic technologies. Secondly, a lack of standardization in ontologies, which would enable interoperability and thirdly, a lack of good tooling support.

Integrated care programmes for adults with chronic conditions: a meta-review.

OBJECTIVE To review systematic reviews and meta-analyses of integrated care programmes in chronically ill patients, with a focus on methodological quality, elements of integration assessed and effects reported. DESIGN Meta-review of systematic reviews and meta-analyses identified in Medline (1946-March 2012), Embase (1980-March 2012), CINHAL (1981-March 2012) and the Cochrane Library of Systematic Reviews (issue 1, 2012). MAIN OUTCOME MEASURES Methodological quality assessed by the 11-item Assessment of Multiple Systematic Reviews (AMSTAR) checklist; elements of integration assessed using a published list of 10 key principles of integration; effects on patient-centred outcomes, process quality, use of healthcare and costs. RESULTS Twenty-seven systematic reviews were identified; conditions included chronic heart failure (CHF; 12 reviews), diabetes mellitus (DM; seven reviews), chronic obstructive pulmonary disease (COPD; seven reviews) and asthma (five reviews). The median number of AMSTAR checklist items met was five: few reviewers searched for unpublished literature or described the primary studies and interventions in detail. Most reviews covered comprehensive services across the care continuum or standardization of care through inter-professional teams, but organizational culture, governance structure or financial management were rarely assessed. A majority of reviews found beneficial effects of integration, including reduced hospital admissions and re-admissions (in CHF and DM), improved adherence to treatment guidelines (DM, COPD and asthma) or quality of life (DM). Few reviews showed reductions in costs. CONCLUSIONS Systematic reviews of integrated care programmes were of mixed quality, assessed only some components of integration of care, and showed consistent benefits for some outcomes but not others.

Virtual tissue alignment and cutting plane definition--a new method to obtain optimal longitudinal histological sections.

Histomorphometric evaluation of the buccal aspects of periodontal tissues in rodents requires reproducible alignment of maxillae and highly precise sections containing central sections of buccal roots; this is a cumbersome and technically sensitive process due to the small specimen size. The aim of the present report is to describe and analyze a method to transfer virtual sections of micro-computer tomographic (CT)-generated image stacks to the microtome for undecalcified histological processing and to describe the anatomy of the periodontium in rat molars. A total of 84 undecalcified sections of all buccal roots of seven untreated rats was analyzed. The accuracy of section coordinate transfer from virtual micro-CT slice to the histological slice, right-left side differences and the measurement error for linear and angular measurements on micro-CT and on histological micrographs were calculated using the Bland-Altman method, interclass correlation coefficient and the method of moments estimator. Also, manual alignment of the micro-CT-scanned rat maxilla was compared with multiplanar computer-reconstructed alignment. The supra alveolar rat anatomy is rather similar to human anatomy, whereas the alveolar bone is of compact type and the keratinized gingival epithelium bends apical to join the junctional epithelium. The high methodological standardization presented herein ensures retrieval of histological slices with excellent display of anatomical microstructures, in a reproducible manner, minimizes random errors, and thereby may contribute to the reduction of number of animals needed.

Should the standard dimethyl sulfoxide concentration be reduced? Results of a European Group for Blood and Marrow Transplantation prospective noninterventional study on usage and side effects of dimethyl sulfoxide.

BACKGROUND Dimethyl sulfoxide (DMSO) is essential for the preservation of liquid nitrogen-frozen stem cells, but is associated with toxicity in the transplant recipient. STUDY DESIGN AND METHODS In this prospective noninterventional study, we describe the use of DMSO in 64 European Blood and Marrow Transplant Group centers undertaking autologous transplantation on patients with myeloma and lymphoma and analyze side effects after return of DMSO-preserved stem cells. RESULTS While the majority of centers continue to use 10% DMSO, a significant proportion either use lower concentrations, mostly 5 or 7.5%, or wash cells before infusion (some for selected patients only). In contrast, the median dose of DMSO given (20 mL) was much less than the upper limit set by the same institutions (70 mL). In an accompanying statistical analysis of side effects noted after return of DMSO-preserved stem cells, we show that patients in the highest quartile receiving DMSO (mL and mL/kg body weight) had significantly more side effects attributed to DMSO, although this effect was not observed if DMSO was calculated as mL/min. Dividing the myeloma and lymphoma patients each into two equal groups by age we were able to confirm this result in all but young myeloma patients in whom an inversion of the odds ratio was seen, possibly related to the higher dose of melphalan received by young myeloma patients. CONCLUSION We suggest better standardization of preservation method with reduced DMSO concentration and attention to the dose of DMSO received by patients could help reduce the toxicity and morbidity of the transplant procedure.

Comparative assessment of ELISAs using recombinant saposin-like protein 2 and recombinant cathepsin L-1 from Fasciola hepatica for the serodiagnosis of human Fasciolosis.

Two recombinant Fasciola hepatica antigens, saposin-like protein-2 (recSAP2) and cathepsin L-1 (recCL1), were assessed individually and in combination in enzyme-linked immunosorbent assays (ELISA) for the specific serodiagnosis of human fasciolosis in areas of low endemicity as encountered in Central Europe. Antibody detection was conducted using ProteinA/ProteinG (PAG) conjugated to alkaline phosphatase. Test characteristics as well as agreement with results from an ELISA using excretory-secretory products (FhES) from adult stage liver flukes was assessed by receiver operator characteristic (ROC) analysis, specificity, sensitivity, Youdens J and overall accuracy. Cross-reactivity was assessed using three different groups of serum samples from healthy individuals (n=20), patients with other parasitic infections (n=87) and patients with malignancies (n=121). The best combined diagnostic results for recombinant antigens were obtained using the recSAP2-ELISA (87% sensitivity, 99% specificity and 97% overall accuracy) employing the threshold (cut-off) to discriminate between positive and negative reactions that maximized Youdens J. The findings showed that recSAP2-ELISA can be used for the routine serodiagnosis of chronic fasciolosis in clinical laboratories; the use of the PAG-conjugate offers the opportunity to employ, for example, rabbit hyperimmune serum for the standardization of positive controls.

Current trends in cannulation and neuroprotection during surgery of the aortic arch in Europe†‡

OBJECTIVES To conduct a survey across European cardiac centres to evaluate the methods used for cerebral protection during aortic surgery involving the aortic arch. METHODS All European centres were contacted and surgeons were requested to fill out a short, comprehensive questionnaire on an internet-based platform. One-third of more than 400 contacted centres completed the survey correctly. RESULTS The most preferred site for arterial cannulation is the subclavian-axillary, both in acute and chronic presentation. The femoral artery is still frequently used in the acute condition, while the ascending aorta is a frequent second choice in the case of chronic presentation. Bilateral antegrade brain perfusion is chosen by the majority of centres (2/3 of cases), while retrograde perfusion or circulatory arrest is very seldom used and almost exclusively in acute clinical presentation. The same pumping system of the cardio pulmonary bypass is most of the time used for selective cerebral perfusion, and the perfusate temperature is usually maintained between 22 and 26°C. One-third of the centres use lower temperatures. Perfusate flow and pressure are fairly consistent among centres in the range of 10-15 ml/kg and 60 mmHg, respectively. In 60% of cases, barbiturates are added for cerebral protection, while visceral perfusion still receives little attention. Regarding cerebral monitoring, there is a general tendency to use near-infrared spectroscopy associated with bilateral radial pressure measurement. CONCLUSIONS These data represent a snapshot of the strategies used for cerebral protection during major aortic surgery in current practice, and may serve as a reference for standardization and refinement of different approaches.

Quality Control for SP Performance Regarding Patient Portrayal in a High-Stakes OSCE

Introduction Since the quality of patient portrayal of standardized patients (SPs) during an Objective Structured Clinical Exam (OSCE) has a major impact on the reliability and validity of the exam, quality control should be initiated. Literature about quality control of SP’s performance focuses on feedback [1, 2] or completion of checklists [3, 4]. Since we did not find a published instrument meeting our needs for the assessment of patient portrayal, we developed such an instrument after being inspired by others [5] and used it in our high-stakes exam. Methods SP trainers from all five Swiss medical faculties collected and prioritized quality criteria for patient portrayal. Items were revised with the partners twice, based on experiences during OSCEs. The final instrument contains 14 criteria for acting (i.e. adequate verbal and non-verbal expression) and standardization (i.e. verbatim delivery of the first sentence). All partners used the instrument during a high-stakes OSCE. Both, SPs and trainers were introduced to the instrument. The tool was used in training (more than 100 observations) and during the exam (more than 250 observations). FAIR_OSCE The list of items to assess the quality of the simulation by SPs was primarily developed and used to provide formative feedback to the SPs in order to help them to improve their performance. It was therefore named “Feedbackstruckture for the Assessment of Interactive Role play in Objective Structured Clinical Exams (FAIR_OSCE). It was also used to assess the quality of patient portrayal during the exam. The results were calculated for each of the five faculties individually. Formative evaluation was given to the five faculties with individual feedback without revealing results of other faculties other than overall results. Results High quality of patient portrayal during the exam was documented. More than 90% of SP performances were rated to be completely correct or sufficient. An increase in quality of performance between training and exam was noted. In example the rate of completely correct reaction in medical tests increased from 88% to 95%. 95% completely correct reactions together with 4% sufficient reactions add up to 99% of the reactions meeting the requirements of the exam. SP educators using the instrument reported an augmentation of SPs performance induced by the use of the instrument. Disadvantages mentioned were high concentration needed to explicitly observe all criteria and cumbersome handling of the paper-based forms. Conclusion We were able to document a very high quality of SP performance in our exam. The data also indicate that our training is effective. We believe that the high concentration needed using the instrument is well invested, considering the observed augmentation of performance. The development of an iPad based application for the form is planned to address the cumbersome handling of the paper.

FAIR_OSCE – Feedback structure for assessment of interactive roleplay in Objective Structured Clinical Exams

Introduction Since the quality of patient portrayal of standardized patients (SPs) during an Objective Structured Clinical Exam (OSCE) has a major impact on the reliability and validity of the exam, quality control should be initiated. Literature about quality control of SPs’ performance focuses on feedback [1, 2] or completion of checklists [3, 4]. Since we did not find a published instrument meeting our needs for the assessment of patient portrayal, we developed such an instrument after being inspired by others [5] and used it in our high-stakes exam. Project description SP trainers from five medical faculties collected and prioritized quality criteria for patient portrayal. Items were revised twice, based on experiences during OSCEs. The final instrument contains 14 criteria for acting (i.e. adequate verbal and non-verbal expression) and standardization (i.e. verbatim delivery of the first sentence). All partners used the instrument during a high-stakes OSCE. SPs and trainers were introduced to the instrument. The tool was used in training (more than 100 observations) and during the exam (more than 250 observations). Outcome High quality of SPs’ patient portrayal during the exam was documented. More than 90% of SP performances were rated to be completely correct or sufficient. An increase in quality of performance between training and exam was noted. For example, the rate of completely correct reaction in medical tests increased from 88% to 95%. Together with 4% of sufficient performances these 95% add up to 99% of the reactions in medical tests meeting the standards of the exam. SP educators using the instrument reported an augmentation of SPs’ performance induced by the use of the instrument. Disadvantages mentioned were the high concentration needed to observe all criteria and the cumbersome handling of the paper-based forms. Discussion We were able to document a very high quality of SP performance in our exam. The data also indicates that our training is effective. We believe that the high concentration needed using the instrument is well invested, considering the observed enhancement of performance. The development of an iPad-based application for the form is planned to address the cumbersome handling of the paper.

Comparison of gadoteric acid and gadobutrol for detection as well as morphologic and dynamic characterization of lesions on breast dynamic contrast-enhanced magnetic resonance imaging

OBJECTIVE In contrast to conventional breast imaging techniques, one major diagnostic benefit of breast magnetic resonance imaging (MRI) is the simultaneous acquisition of morphologic and dynamic enhancement characteristics, which are based on angiogenesis and therefore provide insights into tumor pathophysiology. The aim of this investigation was to intraindividually compare 2 macrocyclic MRI contrast agents, with low risk for nephrogenic systemic fibrosis, in the morphologic and dynamic characterization of histologically verified mass breast lesions, analyzed by blinded human evaluation and a fully automatic computer-assisted diagnosis (CAD) technique. MATERIALS AND METHODS Institutional review board approval and patient informed consent were obtained. In this prospective, single-center study, 45 women with 51 histopathologically verified (41 malignant, 10 benign) mass lesions underwent 2 identical examinations at 1.5 T (mean time interval, 2.1 days) with 0.1-mmol kg doses of gadoteric acid and gadobutrol. All magnetic resonance images were visually evaluated by 2 experienced, blinded breast radiologists in consensus and by an automatic CAD system, whereas the morphologic and dynamic characterization as well as the final human classification of lesions were performed based on the categories of the Breast imaging reporting and data system MRI atlas. Lesions were also classified by defining their probability of malignancy (morpho-dynamic index; 0%-100%) by the CAD system. Imaging results were correlated with histopathology as gold standard. RESULTS The CAD system coded 49 of 51 lesions with gadoteric acid and gadobutrol (detection rate, 96.1%); initial signal increase was significantly higher for gadobutrol than for gadoteric acid for all and the malignant coded lesions (P < 0.05). Gadoteric acid resulted in more postinitial washout curves and fewer continuous increases of all and the malignant lesions compared with gadobutrol (CAD hot spot regions, P < 0.05). Morphologically, the margins of the malignancies were different between the 2 agents, whereas gadobutrol demonstrated more spiculated and fewer smooth margins (P < 0.05). Lesion classifications by the human observers and by the morpho-dynamic index compared with the histopathologic results did not significantly differ between gadoteric acid and gadobutrol. CONCLUSIONS Macrocyclic contrast media can be reliably used for breast dynamic contrast-enhanced MRI. However, gadoteric acid and gadobutrol differed in some dynamic and morphologic characterization of histologically verified breast lesions in an intraindividual, comparison. Besides the standardization of technical parameters and imaging evaluation of breast MRI, the standardization of the applied contrast medium seems to be important to receive best comparable MRI interpretation.

A collaborative study on larval excretory/secretory antigens of Toxocara canis for the immunodiagnosis of human toxocariasis with ELISA.

Two batches of excretory/secretory (E/S) antigens from second stage larvae of Toxocara canis maintained in vitro were prepared independently in two different laboratories (Zürich and Basel) and analysed in order to obtain information for future efforts to standardize the enzyme-linked immunosorbent assay (ELISA) used for the serodiagnosis of human toxocariasis. SDS-PAGE and "Western-blotting" revealed at least 10 different antigenic components common to the two antigen preparations. However, distinct qualitative and quantitative differences among the two E/S-antigens were observed, since one antigen had a more complex composition than the other. Despite these differences, an accordance of serodiagnosis was obtained in 80% of 25 sera from patients with suspected Toxocara infection tested independently in two different ELISA systems (Basel and Zürich) with the corresponding E/S-antigens. The specificity was 93% as determined (BS-antigen, BS-ELISA) by testing 46 out of 3396 sera from patients with parasitologically proven extra-intestinal helminthic infections. Cross-reactions occurred mainly with sera from patients infected with filariae (5 from 13 cases) exhibiting very high extinction values in their homologous ELISA-system. The reproducibility (intra- and inter-test variations) of two ELISA systems using the corresponding E/S-antigens varied from 5-15%. The results demonstrate that T. canis E/S-antigens may well be applicable for standardization of the ELISA used for the serodiagnosis of human toxocariasis.

Climate sensitivity of Mediterranean pine growth reveals distinct east-west dipole

The European Mediterranean region is governed by a characteristic climate of summer drought that is likely to increase in duration and intensity under predicted climate change. However, large-scale network analyses investigating spatial aspects of pre-instrumental drought variability for this biogeographic zone are still scarce. In this study we introduce 54 mid- to high-elevation tree-ring width (TRW) chronologies comprising 2186 individual series from pine trees (Pinus spp.). This compilation spans a 4000-km east–west transect from Spain to Turkey, and was subjected to quality control and standardization prior to the development of site chronologies. A principal component analysis (PCA) was applied to identify spatial growth patterns during the network's common period 1862–1976, and new composite TRW chronologies were developed and investigated. The PCA reveals a common variance of 19.7% over the 54 Mediterranean pine chronologies. More interestingly, a dipole pattern in growth variability is found between the western (15% explained variance) and eastern (9.6%) sites, persisting back to 1330 AD. Pine growth on the Iberian Peninsula and Italy favours warm early growing seasons, but summer drought is most critical for ring width formation in the eastern Mediterranean region. Synoptic climate dynamics that have been in operation for the last seven centuries have been identified as the driving mechanism of a distinct east–west dipole in the growth variability of Mediterranean pines.