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1.  Gene expression data reveal common pathways that characterize the unifocal nature of ovarian cancer 
American journal of obstetrics and gynecology  2013;209(6):10.1016/j.ajog.2013.08.004.
To evaluate the biologic validity of ovarian cancer (OVCA) screening and early detection efforts and to characterize signaling pathways associated with human cancer metastasis and patient survival.
Study Design
Using genome-wide expression profiling and DNA sequencing, we compared pelvic and matched extra-pelvic implants from 30 patients with advanced-stage OVCA for expression of molecular signaling pathways and p53 gene mutations. Differentially expressed pathways were further evaluated in a series of primary or early-stage versus metastatic or recurrent cancer samples from 389 ovarian, prostate, and oral cancer patients. Metastasis pathways were also evaluated for associations with survival in nine independent clinico-genomic datasets from 1,691 ovarian, breast, colon, brain, and lung cancer and leukemia patients. The inhibitory effects of one pathway (TGF-WNT) on in-vitro OVCA cell migration were studied.
Pelvic and extra-pelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations. However, we identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extra-pelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral, and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P=0.006), colon cancer (1 pathway at P=0.005), and leukemia (P=0.05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration.
Advanced-stage OVCA has a unifocal origin in the pelvis, supporting validity of early detection/screening efforts. Molecular pathways associated with extra-pelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease.
PMCID: PMC3840156  PMID: 23933223
Gene Expression; p53 mutation; Serous Ovarian Cancer; Unifocal
2.  All-Cause Pneumonia Hospitalizations in Children <2 Years Old in Sweden, 1998 to 2012: Impact of Pneumococcal Conjugate Vaccine Introduction 
PLoS ONE  2014;9(11):e112211.
In late 2007, some Swedish County Councils started 7-valent pneumococcal conjugate vaccine (PCV7) implementation for children, and PCV7 was included in the national immunization program in 2009. By 2010, both PCV10 and PCV13 were licensed, and the selection of vaccine was subject to County Councils tenders. This study investigated the impact of the order of PCV introduction into vaccination programs on the incidence of all-cause pneumonia hospitalizations in children <2 years-old.
Using population-based data from the publicly available National Inpatient Registry, the incidence of inpatient pneumonia (ICD-10 J12-J18) hospitalizations by County Councils among children <2 years old was identified between 1998 and 2012. Incidence rate ratios (IRR; 95% CI) were calculated during the nationwide implementation of PCV7 and then between County Councils, as based on the higher-valent vaccine chosen for a program.
There was a lower risk of all-cause pneumonia hospitalization among <2 year-old children following the introduction of PCV7, as compared to the pre-PCV7 period (0.77; 0.63–0.93). A decreased risk of all-cause pneumonia was also observed in the County Councils that followed the order PCV7 then PCV13 (0.82; 0.66–1.01), while no trend was observed in County Councils with a program in the order PCV7 then PCV10 (1.03; 0.82–1.30). When comparing the higher-valent vaccines, there was a 21% (0.79; 0.66–0.96) lower risk for childhood pneumonia hospitalization in County Councils finally using PCV13 as compared to the experience in County Councils that ultimately adopted PCV10.
Among children <2 years-old, all-cause pneumonia hospitalizations were significantly reduced by 23% one to two years after introduction of PCV7 vaccination in Sweden. In those County Councils that next introduced PCV13, a further decline in all-cause pneumonia hospitalization was observed, in contrast to those County Councils that followed with PCV10; this 21% lower risk for childhood pneumonia hospitalization was statistically significant.
PMCID: PMC4224441  PMID: 25379659
3.  The choice of anaesthetic—sevoflurane or propofol—and outcome from cancer surgery: A retrospective analysis 
Upsala Journal of Medical Sciences  2014;119(3):251-261.
Commonly used inhalational hypnotics, such as sevoflurane, are pro-inflammatory, whereas the intravenously administered hypnotic agent propofol is anti-inflammatory and anti-oxidative. A few clinical studies have indicated similar effects in patients. We examined the possible association between patient survival after radical cancer surgery and the use of sevoflurane or propofol anaesthesia.
Patients and methods
Demographic, anaesthetic, and surgical data from 2,838 patients registered for surgery for breast, colon, or rectal cancers were included in a database. This was record-linked to regional clinical quality registers. Cumulative 1- and 5-year overall survival rates were assessed using the Kaplan–Meier method, and estimates were compared between patients given propofol (n = 903) or sevoflurane (n = 1,935). In a second step, Cox proportional hazard models were calculated to assess the risk of death adjusted for potential effect modifiers and confounders.
Differences in overall 1- and 5-year survival rates for all three sites combined were 4.7% (p = 0.004) and 5.6% (p < 0.001), respectively, in favour of propofol. The 1-year survival for patients operated for colon cancer was almost 10% higher after propofol anaesthesia. However, after adjustment for several confounders, the observed differences were not statistically significant.
Propofol anaesthesia might be better in surgery for some cancer types, but the retrospective design of this study, with uneven distributions of several confounders, distorted the picture. These uncertainties emphasize the need for a randomized controlled trial.
PMCID: PMC4116765  PMID: 24857018
Anaesthetics; intravenous; inhalational; neoplasm recurrence; local; epidemiology; survival
4.  The patient safety culture as perceived by staff at two different emergency departments before and after introducing a flow-oriented working model with team triage and lean principles: a repeated cross-sectional study 
Patient safety is of the utmost importance in health care. The patient safety culture in an institution has great impact on patient safety. To enhance patient safety and to design strategies to reduce medical injuries, there is a current focus on measuring the patient safety culture. The aim of the present study was to describe the patient safety culture in an ED at two different hospitals before and after a Quality improvement (QI) project that was aimed to enhance patient safety.
A repeated cross-sectional design, using the Hospital Survey On Patient Safety Culture questionnaire before and after a quality improvement project in two emergency departments at a county hospital and a university hospital. The questionnaire was developed to obtain a better understanding of the patient safety culture of an entire hospital or of specific departments. The Swedish version has 51 questions and 15 dimensions.
At the county hospital, a difference between baseline and follow-up was observed in three dimensions. For two of these dimensions, Team-work within hospital and Communication openness, a higher score was measured at the follow-up. At the university hospital, a higher score was measured at follow-up for the two dimensions Team-work across hospital units and Team-work within hospital.
The result showed changes in the self-estimated patient safety culture, mainly regarding team-work and communication openness. Most of the improvements at follow-up were seen by physicians, and mainly at the county hospital.
PMCID: PMC4105242  PMID: 25005231
Patient safety; Patient safety culture; Patient safety climate; Quality improvement; Team-work
5.  Effects of surgeon variability on oncologic and functional outcomes in a population-based setting 
BMC Urology  2014;14:25.
Oncologic and functional outcomes after radical prostatectomy (RP) can vary between surgeons to a greater extent than is expected by chance. We sought to examine the effects of surgeon variation on functional and oncologic outcomes for patients undergoing RP for prostate cancer in a European center.
The study comprised 1,280 men who underwent open retropubic RP performed by one of nine surgeons at an academic institution in Sweden between 2001 and 2008. Potency and continence outcomes were measured preoperatively and 18 months postoperatively by patient-administered questionnaires. Biochemical recurrence (BCR) was defined as a prostate-specific antigen (PSA) value > 0.2 ng/mL with at least one confirmatory rise. Multivariable random effect models were used to evaluate heterogeneity between surgeons, adjusting for case mix (age, PSA, pathological stage and grade), year of surgery, and surgical experience.
Of 679 men potent at baseline, 647 provided data at 18 months with 122 (19%) reporting potency. We found no evidence for heterogeneity of potency outcomes between surgeons (P = 1). The continence rate for patients at 18 months was 85%, with 836 of the 979 patients who provided data reporting continence. There was statistically significant heterogeneity between surgeons (P = 0.001). We did not find evidence of an association between surgeons’ adjusted probabilities of functional recovery and 5-year probability of freedom from BCR.
Our data support previous studies regarding a large heterogeneity among surgeons in continence outcomes for patients undergoing RP. This indicates that some patients are receiving sub-optimal care. Quality assurance measures involving performance feedback, should be considered. When surgeons are aware of their outcomes, they can improve them to provide better care to patients.
PMCID: PMC3975576  PMID: 24602348
Prostate cancer; Radical prostatectomy; Erectile function; Urinary function
6.  Informatics Methods to Enable Sharing of Quantitative Imaging Research Data 
Magnetic resonance imaging  2012;30(9):1249-1256.
The National Cancer Institute (NCI) Quantitative Research Network (QIN) is a collaborative research network whose goal is to share data, algorithms and research tools to accelerate quantitative imaging research. A challenge is the variability in tools and analysis platforms used in quantitative imaging. Our goal was to understand the extent of this variation and to develop an approach to enable sharing data and to promote reuse of quantitative imaging data in the community.
We performed a survey of the current tools in use by the QIN member sites for representation and storage of their QIN research data including images, image meta-data and clinical data. We identified existing systems and standards for data sharing and their gaps for the QIN use case. We then proposed a system architecture to enable data sharing and collaborative experimentation within the QIN.
There area variety of tools currently used by each QIN institution. We developed a general information system architecture to support the QIN goals. We also describe the remaining architecture gaps we are developing to enable members to share research images and image meta-data across the network.
As a research network, the QIN will stimulate quantitative imaging research by pooling data, algorithms and research tools. However, there are gaps in current functional requirements that will need to be met by future informatics development. Special attention must be given to the technical requirements needed to translate these methods into the clinical research workflow to enable validation and qualification of these novel imaging biomarkers.
PMCID: PMC3466343  PMID: 22770688
Quantitative Imaging Network; Data sharing; Imaging Informatics; Research Informatics; Image repository; Image meta-data repository; Clinical data repository; System architecture
7.  QIN “Radiomics: The Process and the Challenges” 
Magnetic resonance imaging  2012;30(9):1234-1248.
“Radiomics” refers to the extraction and analysis of large amounts of advanced quantitative imaging features with high throughput from medical images obtained with computed tomography (CT), positron emission tomography (PET) or magnetic resonance imaging (MRI). Importantly, these data are designed to be extracted from standard-of-care images, leading to a very large potential subject pool. Radiomic data are in a mineable form that can be used to build descriptive and predictive models relating image features to phenotypes or gene-protein signatures. The core hypothesis of radiomics is that these models, which can include biological or medical data, can provide valuable diagnostic, prognostic or predictive information. The radiomics enterprise can be divided into distinct processes, each with its own challenges that need to be overcome: (i) image acquisition and reconstruction (ii) image segmentation and rendering (iii) feature extraction and feature qualification (iv) databases and data sharing for eventual (v) ad hoc informatic analyses. Each of these individual processes poses unique challenges. For example, optimum protocols for image acquisition and reconstruction have to be identified and harmonized. Also, segmentations have to be robust and involve minimal operator input. Features have to be generated that robustly reflect the complexity of the individual volumes, but cannot be overly complex or redundant. Furthermore, informatics databases that allow incorporation of image features and image annotations, along with medical and genetic data have to be generated. Finally, the statistical approaches to analyze these data have to be optimized, as radiomics is not a mature field of study. Each of these processes will be discussed in turn, as well as some of their unique challenges and proposed approaches to solve them. The focus of this article will be on images of non-small cell lung cancer, NSCLC.
PMCID: PMC3563280  PMID: 22898692
Radiomics; Imaging; Image features; Tumor; Segmentation
8.  Iterative rank-order normalization of gene expression microarray data 
BMC Bioinformatics  2013;14:153.
Many gene expression normalization algorithms exist for Affymetrix GeneChip microarrays. The most popular of these is RMA, primarily due to the precision and low noise produced during the process. A significant strength of this and similar approaches is the use of the entire set of arrays during both normalization and model-based estimation of signal. However, this leads to differing estimates of expression based on the starting set of arrays, and estimates can change when a single, additional chip is added to the set. Additionally, outlier chips can impact the signals of other arrays, and can themselves be skewed by the majority of the population.
We developed an approach, termed IRON, which uses the best-performing techniques from each of several popular processing methods while retaining the ability to incrementally renormalize data without altering previously normalized expression. This combination of approaches results in a method that performs comparably to existing approaches on artificial benchmark datasets (i.e. spike-in) and demonstrates promising improvements in segregating true signals within biologically complex experiments.
By combining approaches from existing normalization techniques, the IRON method offers several advantages. First, IRON normalization occurs pair-wise, thereby avoiding the need for all chips to be normalized together, which can be important for large data analyses. Secondly, the technique does not require similarity in signal distribution across chips for normalization, which can be important for maintaining biologically relevant differences in a heterogeneous background. Lastly, IRON introduces fewer post-processing artifacts, particularly in data whose behavior violates common assumptions. Thus, the IRON method provides a practical solution to common needs of expression analysis. A software implementation of IRON is available at [].
PMCID: PMC3651355  PMID: 23647742
Microarray; Expression; Normalization; Affymetrix; GeneChip
9.  DNA Methylation Profiling across the Spectrum of HPV-Associated Anal Squamous Neoplasia 
PLoS ONE  2012;7(11):e50533.
Changes in host tumor genome DNA methylation patterns are among the molecular alterations associated with HPV-related carcinogenesis. However, there is little known about the epigenetic changes associated specifically with the development of anal squamous cell cancer (SCC). We sought to characterize broad methylation profiles across the spectrum of anal squamous neoplasia.
Methodology/Principal Findings
Twenty-nine formalin-fixed paraffin embedded samples from 24 patients were evaluated and included adjacent histologically normal anal mucosa (NM; n = 3), SCC-in situ (SCC-IS; n = 11) and invasive SCC (n = 15). Thirteen women and 11 men with a median age of 44 years (range 26–81) were included in the study. Using the SFP10 LiPA HPV-typing system, HPV was detected in at least one tissue from all patients with 93% (27/29) being positive for high-risk HPV types and 14 (93%) of 15 invasive SCC tissues testing positive for HPV 16. Bisulfite-modified DNA was interrogated for methylation at 1,505 CpG loci representing 807 genes using the Illumina GoldenGate Methylation Array. When comparing the progression from normal anal mucosa and SCC-IS to invasive SCC, 22 CpG loci representing 20 genes demonstrated significant differential methylation (p<0.01). The majority of differentially methylated gene targets occurred at or close to specific chromosomal locations such as previously described HPV methylation “hotspots” and viral integration sites.
We have identified a panel of differentially methlylated CpG loci across the spectrum of HPV-associated squamous neoplasia of the anus. To our knowledge, this is the first reported application of large-scale high throughput methylation analysis for the study of anal neoplasia. Our findings support further investigations into the role of host-genome methylation in HPV-associated anal carcinogenesis with implications towards enhanced diagnosis and screening strategies.
PMCID: PMC3511539  PMID: 23226306
10.  12-Chemokine Gene Signature Identifies Lymph Node-like Structures in Melanoma: Potential for Patient Selection for Immunotherapy? 
Scientific Reports  2012;2:765.
We have interrogated a 12-chemokine gene expression signature (GES) on genomic arrays of 14,492 distinct solid tumors and show broad distribution across different histologies. We hypothesized that this 12-chemokine GES might accurately predict a unique intratumoral immune reaction in stage IV (non-locoregional) melanoma metastases. The 12-chemokine GES predicted the presence of unique, lymph node-like structures, containing CD20+ B cell follicles with prominent areas of CD3+ T cells (both CD4+ and CD8+ subsets). CD86+, but not FoxP3+, cells were present within these unique structures as well. The direct correlation between the 12-chemokine GES score and the presence of unique, lymph nodal structures was also associated with better overall survival of the subset of melanoma patients. The use of this novel 12-chemokine GES may reveal basic information on in situ mechanisms of the anti-tumor immune response, potentially leading to improvements in the identification and selection of melanoma patients most suitable for immunotherapy.
PMCID: PMC3479449  PMID: 23097687
11.  Social differences in lung cancer management and survival in South East England: a cohort study 
BMJ Open  2012;2(3):e001048.
To examine possible social variations in lung cancer survival and assess if any such gradients can be attributed to social differences in comorbidity, stage at diagnosis or treatment.
Population-based cohort identified in the Thames Cancer Registry.
South East England.
15 582 lung cancer patients diagnosed between 2006 and 2008.
Main outcome measures
Stage at diagnosis, surgery, radiotherapy, chemotherapy and survival.
The likelihood of being diagnosed as having early-stage disease did not vary by socioeconomic quintiles (p=0.58). In early-stage non-small-cell lung cancer, the likelihood of undergoing surgery was lowest in the most deprived group. There were no socioeconomic differences in the likelihood of receiving radiotherapy in stage III disease, while in advanced disease and in small-cell lung cancer, receipt of chemotherapy differed over socioeconomic quintiles (p<0.01). In early-stage disease and following adjustment for confounders, the HR between the most deprived and the most affluent group was 1.24 (95% CI 0.98 to 1.56). Corresponding estimates in stage III and advanced disease or small-cell lung cancer were 1.16 (95% CI 1.01 to 1.34) and 1.12 (95% CI 1.05 to 1.20), respectively. In early-stage disease, the crude HR between the most deprived and the most affluent group was approximately 1.4 and constant through follow-up, while in patients with advanced disease or small-cell lung cancer, no difference was detectable after 3 months.
We observed socioeconomic variations in management and survival in patients diagnosed as having lung cancer in South East England between 2006 and 2008, differences which could not fully be explained by social differences in stage at diagnosis, co-morbidity and treatment. The survival observed in the most affluent group should set the target for what is achievable for all lung cancer patients, managed in the same healthcare system.
Article summary
Article focus
Social differences in management and survival in lung cancer patients.
Particular focus on possible social variations in lung cancer survival and assess if any such gradients can be attributed to social differences in co-morbidity, stage at diagnosis or treatment.
Key messages
There were no detectable socioeconomic differences in stage at diagnosis among lung cancer patients in South East England between 2006 and 2008.
Socioeconomic differences in lung cancer management and survival existed. The observed inequalities in survival could not fully be explained by social differences in stage at diagnosis, co-morbidity and treatment factors.
In early-stage disease, social gradients in survival existed throughout follow-up, whereas in advanced disease, variations in survival were confined to the period immediately after diagnosis.
Strengths and limitations of this study
Strengths included the population-based cohort design. The material at hand allowed analyses that accounted for co-morbidity, stage at diagnosis and treatment factors.
Limitations included the absence of data on performance status, forced expiratory volume, smoking history and lifestyle factors.
PMCID: PMC3367157  PMID: 22637374
12.  The impact of CPR and AED training on healthcare professionals' self-perceived attitudes to performing resuscitation 
Healthcare professionals have shown concern about performing mouth-to-mouth ventilation due to the risks to themselves with the procedure. However, little is known about healthcare professionals' fears and attitudes to start CPR and the impact of training.
To examine whether there were any changes in the attitudes among healthcare professionals to performing CPR from before to after training.
Healthcare professionals from two Swedish hospitals were asked to answer a questionnaire before and after training. The questions were relating to physical and mental discomfort and attitudes to CPR. Statistical analysis used was generalized McNemar's test.
Overall, there was significant improvement in 10 of 11 items, reflecting various aspects of attitudes to CPR.
All groups of health care professionals (physicians, nurses, assistant nurses, and "others" = physiotherapists, occupational therapists, social welfare officers, psychologists, biomedical analysts) felt more secure in CPR knowledge after education. In other aspects, such as anxiety prior to a possible cardiac arrest, only nurses and assistant nurses improved.
The concern about being infected, when performing mouth to mouth ventilation, was reduced with the most marked reduction in physicians (75%; P < 0.001).
In this hospital-based setting, we found a positive outcome of education and training in CPR concerning healthcare professionals' attitudes to perform CPR. They felt more secure in their knowledge of cardiopulmonary resuscitation. In some aspects of attitudes to resuscitation nurses and assistant nurses appeared to be the groups that were most markedly influenced. The concern of being infected by a disease was low.
PMCID: PMC3352321  PMID: 22480164
Education; Cardiopulmonary resuscitation; Attitude; Defibrillators; Health personnel
13.  Occupational affiliation does not influence practical skills in cardiopulmonary resuscitation for in-hospital healthcare professionals 
D-CPR (Defibrillator Cardiopulmonary Resuscitation) is a technique for optimal basic life support during cardiopulmonary resuscitation (CPR). Guidelines recommend that healthcare professionals can perform CPR with competence. How CPR training and provision is organized varies between hospitals, and it is our impression that in Sweden this has generally improved during the last 15-20 years. However, some hospitals still do not have any AED (Automated External Defibrillators). The aim was to investigate potential differences in practical skills between different healthcare professions before and after training in D-CPR.
Seventy-four healthcare professionals were video recorded and evaluated for adherence to a modified Cardiff Score. A Laerdal Resusci Anne manikin in connection to PC Skill reporting System was used to evaluate CPR quality. A simulated CPR situation was accomplished during a 5-10 min scenario of ventricular fibrillation. Paired and unpaired statistical methods were used to examine differences within and between occupations with respect to the intervention.
There were no differences in skills among the different healthcare professions, except for compressions per minute. In total, the number of compression per minute and depth improved for all groups (P < 0.001). In total, 41% of the participants used AED before and 96% of the participants used AED after the intervention (P < 0.001). Before intervention, it took a median time of 120 seconds until the AED was used; after the intervention, it took 82 seconds.
Nearly all healthcare professionals learned to use the AED. There were no differences in CPR skill performances among the different healthcare professionals.
PMCID: PMC3026050  PMID: 21235765
14.  Sequence signature analysis of chromosome identity in three Drosophila species 
BMC Bioinformatics  2005;6:158.
All eukaryotic organisms need to distinguish each of their chromosomes. A few protein complexes have been described that recognise entire, specific chromosomes, for instance dosage compensation complexes and the recently discovered autosome-specific Painting of Fourth (POF) protein in Drosophila. However, no sequences have been found that are chromosome-specific and distributed over the entire length of the respective chromosome. Here, we present a new, unbiased, exhaustive computational method that was used to probe three Drosophila genomes for chromosome-specific sequences.
By combining genome annotations and cytological data with multivariate statistics related to three Drosophila genomes we found sequence signatures that distinguish Muller's F-elements (chromosome 4 in D. melanogaster) from all other chromosomes in Drosophila that are not attributable to differences in nucleotide composition, simple sequence repeats or repeated elements. Based on these signatures we identified complex motifs that are strongly overrepresented in the F-elements and found indications that the D. melanogaster motif may be involved in POF-binding to the F-element. In addition, the X-chromosomes of D. melanogaster and D. yakuba can be distinguished from the other chromosomes, albeit to a lesser extent. Surprisingly, the conservation of the F-element sequence signatures extends not only between species separated by approximately 55 Myr, but also linearly along the sequenced part of the F-elements.
Our results suggest that chromosome-distinguishing features are not exclusive to the sex chromosomes, but are also present on at least one autosome (the F-element) in Drosophila.
PMCID: PMC1181806  PMID: 15975141

Results 1-14 (14)