Colorectal Cancer Classification and Cell Heterogeneity: A Systems Oncology Approach.

Colorectal cancer is a heterogeneous disease that manifests through diverse clinical scenarios. During many years, our knowledge about the variability of colorectal tumors was limited to the histopathological analysis from which generic classifications associated with different clinical expectations are derived. However, currently we are beginning to understand that under the intense pathological and clinical variability of these tumors there underlies strong genetic and biological heterogeneity. Thus, with the increasing available information of inter-tumor and intra-tumor heterogeneity, the classical pathological approach is being displaced in favor of novel molecular classifications. In the present article, we summarize the most relevant proposals of molecular classifications obtained from the analysis of colorectal tumors using powerful high throughput techniques and devices. We also discuss the role that cancer systems biology may play in the integration and interpretation of the high amount of data generated and the challenges to be addressed in the future development of precision oncology. In addition, we review the current state of implementation of these novel tools in the pathological laboratory and in clinical practice.

Classification and clinical behavior of blastic plasmacytoid dendritic cell neoplasms according to their maturation-associated immunophenotypic profile.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whose diagnosis can be difficult to achieve due to its clinical and biological heterogeneity, as well as its overlapping features with other hematologic malignancies. In this study we investigated whether the association between the maturational stage of tumor cells and the clinico-biological and prognostic features of the disease, based on the analysis of 46 BPDCN cases classified into three maturation-associated subgroups on immunophenotypic grounds. Our results show that blasts from cases with an immature plasmacytoid dendritic cell (pDC) phenotype exhibit an uncommon CD56- phenotype, coexisting with CD34+ non-pDC tumor cells, typically in the absence of extramedullary (e.g. skin) disease at presentation. Conversely, patients with a more mature blast cell phenotype more frequently displayed skin/extramedullary involvement and spread into secondary lymphoid tissues. Despite the dismal outcome, acute lymphoblastic leukemia-type therapy (with central nervous system prophylaxis) and/or allogeneic stem cell transplantation appeared to be the only effective therapies. Overall, our findings indicate that the maturational profile of pDC blasts in BPDCN is highly heterogeneous and translates into a wide clinical spectrum -from acute leukemia to mature lymphoma-like behavior-, which may also lead to variable diagnosis and treatment.

Grain size analyses in tin-lead glazes based on 2d-sections

A problem in the archaeometric classification of Catalan Renaissance pottery is the fact, thatthe clay supply of the pottery workshops was centrally organized by guilds, and thereforeusually all potters of a single production centre produced chemically similar ceramics.However, analysing the glazes of the ware usually a large number of inclusions in the glaze isfound, which reveal technological differences between single workshops. These inclusionshave been used by the potters in order to opacify the transparent glaze and to achieve a whitebackground for further decoration.In order to distinguish different technological preparation procedures of the single workshops,at a Scanning Electron Microscope the chemical composition of those inclusions as well astheir size in the two-dimensional cut is recorded. Based on the latter, a frequency distributionof the apparent diameters is estimated for each sample and type of inclusion.Following an approach by S.D. Wicksell (1925), it is principally possible to transform thedistributions of the apparent 2D-diameters back to those of the true three-dimensional bodies.The applicability of this approach and its practical problems are examined using differentways of kernel density estimation and Monte-Carlo tests of the methodology. Finally, it istested in how far the obtained frequency distributions can be used to classify the pottery

Medulloblastomas in adults : lessons from pediatrics

Buts de la revue: Les Médulloblastomes sont des tumeurs rares chez l'adulte. Le traitement habituel comprend une radiothérapie de tout l'axe cranio-spinal avec ou sans chimiothérapie. Beaucoup d'efforts sont actuellement entrepris pour mieux comprendre la biologie tumorale, afin de mieux stratifier les patients en différents groupes à risques et de les traiter en fonction. Cette revue discute les nouveaux facteurs de risques cliniques et moléculaires qui peuvent aider à optimiser le traitement des patients adultes avec des médulloblastomes. Découvertes récentes: Jusqu'à présent les patients étaient divisés en groupes à bas risque ou à haut risque sur la base de facteurs cliniques (âge, maladie résiduelle après chirurgie, dissémination dans le système nerveux central et l'histologie). Cette classification devrait être complétée par des facteurs pronostics moléculaires. Le profilage de l'expression des gènes a permis d'identifier six sous-groupes moléculaires de médulloblastomes. Le WNT sous-groupe montre une activation des gènes de la voie de signalisation WNT/wingless avec des mutations fréquentes du gène CNNTB1, une perte du chromosome 6 et une accumulation de β-catenine nucléaire. Ce sous-groupe est rencontré le plus souvent chez les enfants avec des médulloblastomes avec une histologie classique. Ils ont un bon pronostic. Une activation de la voie de signalisation du sonic hedgehog montre des mutations fréquentes des gènes PTCH et SUFU, une perte du 9q et une positivité pour GLI1 et SFRP1 et est rencontré plus fréquemment chez les enfants de moins de 3 ans et chez les adultes. Ce sous-groupe est souvent associé à une histologie de type desmoplastique. D'autre sous-groupes sont moins bien délimités et présentent des caractéristiques qui se chevauchent. Cependant une amplification MYC/MYCN, un gain du 17p et une histologie de type grandes cellules/anaplasique sont des facteurs de mauvais pronostic. Résumé: Des nouveaux sous-groupes moléculaires vont dorénavant aider à mieux adapter les traitements aux différents groupes de risque et permettront à développer de nouvelles thérapies ciblées. Des études prospectives et si possibles randomisées devraient être effectuées comprenant une stratification dans des sous-groupes moléculaires, afin d'identifier au mieux le meilleur traitement pour chaque groupe à risque.

Phylogenetic approach reveals that virus genotype largely determines HIV set-point viral load.

HIV virulence, i.e. the time of progression to AIDS, varies greatly among patients. As for other rapidly evolving pathogens of humans, it is difficult to know if this variance is controlled by the genotype of the host or that of the virus because the transmission chain is usually unknown. We apply the phylogenetic comparative approach (PCA) to estimate the heritability of a trait from one infection to the next, which indicates the control of the virus genotype over this trait. The idea is to use viral RNA sequences obtained from patients infected by HIV-1 subtype B to build a phylogeny, which approximately reflects the transmission chain. Heritability is measured statistically as the propensity for patients close in the phylogeny to exhibit similar infection trait values. The approach reveals that up to half of the variance in set-point viral load, a trait associated with virulence, can be heritable. Our estimate is significant and robust to noise in the phylogeny. We also check for the consistency of our approach by showing that a trait related to drug resistance is almost entirely heritable. Finally, we show the importance of taking into account the transmission chain when estimating correlations between infection traits. The fact that HIV virulence is, at least partially, heritable from one infection to the next has clinical and epidemiological implications. The difference between earlier studies and ours comes from the quality of our dataset and from the power of the PCA, which can be applied to large datasets and accounts for within-host evolution. The PCA opens new perspectives for approaches linking clinical data and evolutionary biology because it can be extended to study other traits or other infectious diseases.

Improved accuracy of co-morbidity coding over time after the introduction of ICD-10 administrative data.

BACKGROUND: Co-morbidity information derived from administrative data needs to be validated to allow its regular use. We assessed evolution in the accuracy of coding for Charlson and Elixhauser co-morbidities at three time points over a 5-year period, following the introduction of the International Classification of Diseases, 10th Revision (ICD-10), coding of hospital discharges.METHODS: Cross-sectional time trend evaluation study of coding accuracy using hospital chart data of 3'499 randomly selected patients who were discharged in 1999, 2001 and 2003, from two teaching and one non-teaching hospital in Switzerland. We measured sensitivity, positive predictive and Kappa values for agreement between administrative data coded with ICD-10 and chart data as the 'reference standard' for recording 36 co-morbidities.RESULTS: For the 17 the Charlson co-morbidities, the sensitivity - median (min-max) - was 36.5% (17.4-64.1) in 1999, 42.5% (22.2-64.6) in 2001 and 42.8% (8.4-75.6) in 2003. For the 29 Elixhauser co-morbidities, the sensitivity was 34.2% (1.9-64.1) in 1999, 38.6% (10.5-66.5) in 2001 and 41.6% (5.1-76.5) in 2003. Between 1999 and 2003, sensitivity estimates increased for 30 co-morbidities and decreased for 6 co-morbidities. The increase in sensitivities was statistically significant for six conditions and the decrease significant for one. Kappa values were increased for 29 co-morbidities and decreased for seven.CONCLUSIONS: Accuracy of administrative data in recording clinical conditions improved slightly between 1999 and 2003. These findings are of relevance to all jurisdictions introducing new coding systems, because they demonstrate a phenomenon of improved administrative data accuracy that may relate to a coding 'learning curve' with the new coding system.

A Novel Breast Tissue Density Classification Methodology

It has been shown that the accuracy of mammographic abnormality detection methods is strongly dependent on the breast tissue characteristics, where a dense breast drastically reduces detection sensitivity. In addition, breast tissue density is widely accepted to be an important risk indicator for the development of breast cancer. Here, we describe the development of an automatic breast tissue classification methodology, which can be summarized in a number of distinct steps: 1) the segmentation of the breast area into fatty versus dense mammographic tissue; 2) the extraction of morphological and texture features from the segmented breast areas; and 3) the use of a Bayesian combination of a number of classifiers. The evaluation, based on a large number of cases from two different mammographic data sets, shows a strong correlation ( and 0.67 for the two data sets) between automatic and expert-based Breast Imaging Reporting and Data System mammographic density assessment

Implementing statistical learning methods through Bayesian networks (Part 2): bayesian evaluations for results of black toner analyses in forensic document examination

This paper presents and discusses the use of Bayesian procedures - introduced through the use of Bayesian networks in Part I of this series of papers - for 'learning' probabilities from data. The discussion will relate to a set of real data on characteristics of black toners commonly used in printing and copying devices. Particular attention is drawn to the incorporation of the proposed procedures as an integral part in probabilistic inference schemes (notably in the form of Bayesian networks) that are intended to address uncertainties related to particular propositions of interest (e.g., whether or not a sample originates from a particular source). The conceptual tenets of the proposed methodologies are presented along with aspects of their practical implementation using currently available Bayesian network software.

Document Tècnic de l'Edificació i annexes : cobertes, lluernaris i claraboies

El document és una recopilació de tota una informació prèvia per tal derealitzar un Document Tècnic de l’Edificació que s’ha servit de guia de les actuals NTE(Normes Tecnològiques de l’Edificació), però sense posar en dubte les NTE ni substituir-les.Aquest DTE consisteix en refer la NTE-QLC-1973 (NormaTecnològica de l’Edificació – Cubiertas Lucernarios Claraboyas), que passaràanomenar-se DTE-CLC-CP / CLC-CT. (Document Tècnic de l’Edificació – CobertesLluernaris Claraboies – Claraboies de Catàleg / Claraboies Tubulars).El meu interès per la llum natural va fer que em decidís per triar el tema de lesClaraboies, i el meu estudi es base en les claraboies de catàleg, de les quals ja parlade l’actual NTE i, a més a més, el DTE incorpora un nou tipus de claraboia com són lestubulars

Iowa Airport Directory, 2003 ***NOTE*** This document is for historical viewing, the internal information is no longer current or accurate! ***NOTE*** Current information can be found at http://www.iowadot.gov/aviation/aircraftregistration/registration.aspx ***NOTE***

Iowa has 8 commercial service airports and 105 general aviation airports, of which three serve as reliever airports. ***NOTE*** This document is for historical viewing, the internal information is no longer current or accurate! ***NOTE*** Current information can be found at http://www.iowadot.gov/aviation/aircraftregistration/registration.aspx ***NOTE***

A novel method for automated classification of epileptiform activity in the human electroencephalogram-based on independent component analysis.

Diagnosis of several neurological disorders is based on the detection of typical pathological patterns in the electroencephalogram (EEG). This is a time-consuming task requiring significant training and experience. Automatic detection of these EEG patterns would greatly assist in quantitative analysis and interpretation. We present a method, which allows automatic detection of epileptiform events and discrimination of them from eye blinks, and is based on features derived using a novel application of independent component analysis. The algorithm was trained and cross validated using seven EEGs with epileptiform activity. For epileptiform events with compensation for eyeblinks, the sensitivity was 65 +/- 22% at a specificity of 86 +/- 7% (mean +/- SD). With feature extraction by PCA or classification of raw data, specificity reduced to 76 and 74%, respectively, for the same sensitivity. On exactly the same data, the commercially available software Reveal had a maximum sensitivity of 30% and concurrent specificity of 77%. Our algorithm performed well at detecting epileptiform events in this preliminary test and offers a flexible tool that is intended to be generalized to the simultaneous classification of many waveforms in the EEG.

Distribution des durées de séjour par Diagnosis Related Group

Ce cahier fournit les principales informations concernant les durées de séjour et le nombre de sorties observées dans 33 hôpitaux suisses pour l'années 1984. La description des clientèles hospitalières est fondée sur les "Diagnosis Related Groups" (DRG), qui forment une classification de 472 groupes de patients hospitalisés. [Auteurs, p. 1]

Trends in hospital discharges, management and in-hospital mortality from acute myocardial infarction in Switzerland between 1998 and 2008.

BACKGROUND: Since the late nineties, no study has assessed the trends in management and in-hospital outcome of acute myocardial infarction (AMI) in Switzerland. Our objective was to fill this gap. METHODS: Swiss hospital discharge database for years 1998 to 2008. AMI was defined as a primary discharge diagnosis code I21 according to the ICD10 classification. Invasive treatments and overall in-hospital mortality were assessed. RESULTS: Overall, 102,729 hospital discharges with a diagnosis of AMI were analyzed. The percentage of hospitalizations with a stay in an Intensive Care Unit decreased from 38.0% in 1998 to 36.2% in 2008 (p for trend < 0.001). Percutaneous revascularizations increased from 6.0% to 39.9% (p for trend < 0.001). Bare stents rose from 1.3% to 16.6% (p for trend < 0.001). Drug eluting stents appeared in 2004 and increased to 23.5% in 2008 (p for trend < 0.001). Coronary artery bypass graft increased from 1.0% to 3.0% (p for trend < 0.001). Circulatory assistance increased from 0.2% to 1.7% (p for trend < 0.001). Among patients managed in a single hospital (not transferred), seven-day and total in-hospital mortality decreased from 8.0% to 7.0% (p for trend < 0.01) and from 11.2% to 10.1%, respectively. These changes were no longer significant after multivariate adjustment for age, gender, region, revascularization procedures and transfer type. After multivariate adjustment, differing trends in revascularization procedures and in in-hospital mortality were found according to the geographical region considered. CONCLUSION: In Switzerland, a steep rise in hospital discharges and in revascularization procedures for AMI occurred between 1998 and 2008. The increase in revascularization procedures could explain the decrease in in-hospital mortality rates.