Neurological complications after stem cell transplantation in children

Allogeneic haematopoietic stem cell transplantation (HSCT) is a well established method used in the treatment of a number of benign and malignant blood diseases, inborn errors of metabolism and severe congenital immunodeficiency syndromes. Around 60 children are transplanted in Sweden every year. Every HSCT carries a risk of different types of complications for the patient. As the success rate and survival after HSCT increases, the prevention of neurological complications and their long-term sequelae has particular significance in the paediatric patient group. Paper I describes the acute neurological complications after HSCT in144 paediatric patients transplanted between 1995 and 2002 at the Karolinska University Hospital-Huddinge. The group of 19 patients (13%) who suffered from neurological complications within three months after HSCT had an elevated risk of death within the first year after HSCT. An increasing number of positive herpesvirus serologies and CMV sero-positivity before HSCT as well as electrolyte-disturbances, high blood pressure and elevated bilirubin during the first three months after HSCT increased the risk of neurological complications. The most common complication was seizures and the most frequent causes of these complications were infection and encephalopathy. In several patients the exact aetiology of the complication could not be determined. Intrathecal chemotherapy is given as prophylaxis to high risk patients after HSCT to lower the risk of CNS relapse of malignant disease. The treatment increases the risk for acute and late onset neurological complications. However the need for this treatment is questioned as advances in primary oncologic treatment before HSCT has substantially decreased the risk for CNS relapse. In Paper II and III we retrospectively compared patients who received intrathecal therapy after HSCT to a group who was not given this treatment. The primary aim was to examine if there was a reduction in CNS relapses in the group given intrathecal chemoprophylaxis. In Paper II 120 patients transplanted 1992 to 2005 were included in the study. In Paper III 397 patients transplanted 1992 to 2006 were studied. Neither of the studies could identify a difference in the prevalence of CNS relapses, other types of relapses, mortality or a difference in the prevalence of neurological complications between the two groups. The study results have resulted in a revision of the clinical protocol for intrathecal chemoprophylaxis after HSCT in many centres. In Paper IV we addressed the fact that infections are a common cause of neurological complications after HSCT and that the exact cause of many complications are unknown. We aimed to study the prevalence and the clinical symptoms of CNS infections by human polyomavirus (HPyV) within a year after HSCT. We analysed retrospectively the CSF of 20 HSCT patients with neurological complications for five different HPyV; JC-, BK-, KI-, WU-, and MCPyV. JC- and BK-PyV are known neurotropic viruses discovered in the 1970`s. KI-, WU- and MCPyV are more recently discovered viruses where the neurotropic ability is not yet known. The PCR analyses of the 20 CSF-samples were negative for all the five viruses. More studies need to be done to determine the significance of the new HPyV in complications after HSCT. Conclusion: our studies have contributed with a small piece of knowledge in the struggle to prevent neurological complications after HSCT. Further research is though needed to identify additional risk factors and further improve treatment so that less neurotoxic treatments are needed

Buried shallow fault slip from the South Napa earthquake revealed by near-field geodesy.

Earthquake-related fault slip in the upper hundreds of meters of Earths surface has remained largely unstudied because of challenges measuring deformation in the near field of a fault rupture. We analyze centimeter-scale accuracy mobile laser scanning (MLS) data of deformed vine rows within ±300 m of the principal surface expression of the M (magnitude) 6.0 2014 South Napa earthquake. Rather than assuming surface displacement equivalence to fault slip, we invert the near-field data with a model that allows for, but does not require, the fault to be buried below the surface. The inversion maps the position on a preexisting fault plane of a slip front that terminates ~3 to 25 m below the surface coseismically and within a few hours postseismically. The lack of surface-breaching fault slip is verified by two trenches. We estimate near-surface slip ranging from ~0.5 to 1.25 m. Surface displacement can underestimate fault slip by as much as 30%. This implies that similar biases could be present in short-term geologic slip rates used in seismic hazard analyses. Along strike and downdip, we find deficits in slip: The along-strike deficit is erased after ~1 month by afterslip. We find no evidence of off-fault deformation and conclude that the downdip shallow slip deficit for this event is likely an artifact. As near-field geodetic data rapidly proliferate and will become commonplace, we suggest that analyses of near-surface fault rupture should also use more sophisticated mechanical models and subsurface geomechanical tests

Radiomics of Lung Nodules: A Multi-Institutional Study of Robustness and Agreement of Quantitative Imaging Features.

Radiomics is to provide quantitative descriptors of normal and abnormal tissues during classification and prediction tasks in radiology and oncology. Quantitative Imaging Network members are developing radiomic "feature" sets to characterize tumors, in general, the size, shape, texture, intensity, margin, and other aspects of the imaging features of nodules and lesions. Efforts are ongoing for developing an ontology to describe radiomic features for lung nodules, with the main classes consisting of size, local and global shape descriptors, margin, intensity, and texture-based features, which are based on wavelets, Laplacian of Gaussians, Law's features, gray-level co-occurrence matrices, and run-length features. The purpose of this study is to investigate the sensitivity of quantitative descriptors of pulmonary nodules to segmentations and to illustrate comparisons across different feature types and features computed by different implementations of feature extraction algorithms. We calculated the concordance correlation coefficients of the features as a measure of their stability with the underlying segmentation; 68% of the 830 features in this study had a concordance CC of ≥0.75. Pairwise correlation coefficients between pairs of features were used to uncover associations between features, particularly as measured by different participants. A graphical model approach was used to enumerate the number of uncorrelated feature groups at given thresholds of correlation. At a threshold of 0.75 and 0.95, there were 75 and 246 subgroups, respectively, providing a measure for the features' redundancy

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Comparative effectiveness of lifestyle interventions on cardiovascular risk factors among a Dutch overweight working population: A randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Overweight (Body Mass Index [BMI] ≥ 25 kg/m²) and obesity (BMI≥ 30 kg/m²) are associated with increased cardiovascular risk, posing a considerable burden to public health. The main aim of this study was to investigate lifestyle intervention effects on cardiovascular risk factors in healthy overweight employees.</p> <p>Methods</p> <p>Participants were 276 healthy overweight employees (69.2% male; mean age 44.0 years [SD 9.2]; mean BMI 29.7 kg/m²[SD 3.1]). They were randomized to one of two intervention groups receiving a six month lifestyle intervention with behavior counseling by phone (phone group) or e-mail (Internet group), or to a control group receiving usual care. Body weight, height, waist circumference, sum of skinfolds, blood pressure, total cholesterol level and predicted aerobic fitness were measured at baseline, at 6 and at 24 months. Regression analyses included the 141 participants with complete data.</p> <p>Results</p> <p>At 6 months a significant favorable effect on total cholesterol level (-0.2 mmol/l, 95%CI -0.5 to -0.0) was observed in the phone group and a trend for improved aerobic fitness (1.9 ml/kg/min, 95%CI -0.2 to 3.9) in the Internet group. At two years, favorable trends for body weight (-2.1 kg, 95%CI -4.4 to 0.2) and aerobic fitness (2.3 ml/kg/min, 95%CI -0.2 to 4.8) were observed in the Internet group.</p> <p>Conclusions</p> <p>The intervention effects were independent of the used communication mode. However short-term results were in favor of the phone group and long-term results in favor of the internet group. Thus, we found limited evidence for our lifestyle intervention to be effective in reducing cardiovascular risk in a group of apparently healthy overweight workers.</p> <p>Trial registration</p> <p><a href="http://www.controlled-trials.com/ISRCTN04265725">ISRCTN04265725</a></p

ALIFE@Work: a randomised controlled trial of a distance counselling lifestyle programme for weight control among an overweight working population [ISRCTN04265725]

BACKGROUND: The prevalence of overweight is increasing and its consequences will cause a major public health burden in the near future. Cost-effective interventions for weight control among the general population are therefore needed. The ALIFE@Work study is investigating a novel lifestyle intervention, aimed at the working population, with individual counselling through either phone or e-mail. This article describes the design of the study and the participant flow up to and including randomisation. METHODS/DESIGN: ALIFE@Work is a controlled trial, with randomisation to three arms: a control group, a phone based intervention group and an internet based intervention group. The intervention takes six months and is based on a cognitive behavioural approach, addressing physical activity and diet. It consists of 10 lessons with feedback from a personal counsellor, either by phone or e-mail, between each lesson. Lessons contain educational content combined with behaviour change strategies. Assignments in each lesson teach the participant to apply these strategies to every day life. The study population consists of employees from seven Dutch companies. The most important inclusion criteria are having a body mass index (BMI) ≥ 25 kg/m(2 )and being an employed adult. Primary outcomes of the study are body weight and BMI, diet and physical activity. Other outcomes are: perceived health; empowerment; stage of change and self-efficacy concerning weight control, physical activity and eating habits; work performance/productivity; waist circumference, sum of skin folds, blood pressure, total blood cholesterol level and aerobic fitness. A cost-utility- and a cost-effectiveness analysis will be performed as well. Physiological outcomes are measured at baseline and after six and 24 months. Other outcomes are measured by questionnaire at baseline and after six, 12, 18 and 24 months. Statistical analyses for short term (six month) results are performed with multiple linear regression. Analyses for long term (two year) results are performed with multiple longitudinal regression. Analyses for cost-effectiveness and cost-utility are done at one and two years, using bootstrapping techniques. DISCUSSION: ALIFE@Work will make a substantial contribution to the development of cost-effective weight control- and lifestyle interventions that are applicable to and attractive for the large population at risk