Aberrant Retinoblastoma (RB)-E2F Transcriptional Regulation Defines Molecular Phenotypes of Osteosarcoma*

PubMed Central

Scott, Milcah C.; Sarver, Aaron L.; Tomiyasu, Hirotaka; Cornax, Ingrid; Van Etten, Jamie; Varshney, Jyotika; O'Sullivan, M. Gerard; Subramanian, Subbaya; Modiano, Jaime F.

2015-01-01

We previously identified two distinct molecular subtypes of osteosarcoma through gene expression profiling. These subtypes are associated with distinct tumor behavior and clinical outcomes. Here, we describe mechanisms that give rise to these molecular subtypes. Using bioinformatic analyses, we identified a significant association between deregulation of the retinoblastoma (RB)-E2F pathway and the molecular subtype with worse clinical outcomes. Xenotransplantation models recapitulated the corresponding behavior for each osteosarcoma subtype; thus, we used cell lines to validate the role of the RB-E2F pathway in regulating the prognostic gene signature. Ectopic RB resets the patterns of E2F regulated gene expression in cells derived from tumors with worse clinical outcomes (molecular phenotype 2) to those comparable with those observed in cells derived from tumors with less aggressive outcomes (molecular phenotype 1), providing a functional association between RB-E2F dysfunction and altered gene expression in osteosarcoma. DNA methyltransferase and histone deacetylase inhibitors similarly reset the transcriptional state of the molecular phenotype 2 cells from a state associated with RB deficiency to one seen with RB sufficiency. Our data indicate that deregulation of RB-E2F pathway alters the epigenetic landscape and biological behavior of osteosarcoma. PMID:26378234

The molecular basis of breast cancer pathological phenotypes.

PubMed

Heng, Yujing J; Lester, Susan C; Tse, Gary Mk; Factor, Rachel E; Allison, Kimberly H; Collins, Laura C; Chen, Yunn-Yi; Jensen, Kristin C; Johnson, Nicole B; Jeong, Jong Cheol; Punjabi, Rahi; Shin, Sandra J; Singh, Kamaljeet; Krings, Gregor; Eberhard, David A; Tan, Puay Hoon; Korski, Konstanty; Waldman, Frederic M; Gutman, David A; Sanders, Melinda; Reis-Filho, Jorge S; Flanagan, Sydney R; Gendoo, Deena Ma; Chen, Gregory M; Haibe-Kains, Benjamin; Ciriello, Giovanni; Hoadley, Katherine A; Perou, Charles M; Beck, Andrew H

2017-02-01

The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or reverse-phase protein assay subtype. Marked nuclear pleomorphism, necrosis, inflammation and a high mitotic count were associated with the basal-like subtype, and had a similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed by use of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of poorly differentiated epithelial tubules was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative breast cancer. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has the potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology, and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

PubMed

Nabors, Louis Burt; Portnow, Jana; Ammirati, Mario; Baehring, Joachim; Brem, Henry; Butowski, Nicholas; Fenstermaker, Robert A; Forsyth, Peter; Hattangadi-Gluth, Jona; Holdhoff, Matthias; Howard, Steven; Junck, Larry; Kaley, Thomas; Kumthekar, Priya; Loeffler, Jay S; Moots, Paul L; Mrugala, Maciej M; Nagpal, Seema; Pandey, Manjari; Parney, Ian; Peters, Katherine; Puduvalli, Vinay K; Ragsdale, John; Rockhill, Jason; Rogers, Lisa; Rusthoven, Chad; Shonka, Nicole; Shrieve, Dennis C; Sills, Allen K; Swinnen, Lode J; Tsien, Christina; Weiss, Stephanie; Wen, Patrick Yung; Willmarth, Nicole; Bergman, Mary Anne; Engh, Anita

2017-11-01

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas. Copyright © 2017 by the National Comprehensive Cancer Network.

miRNA-135b Contributes to Triple Negative Breast Cancer Molecular Heterogeneity: Different Expression Profile in Basal-like Versus non-Basal-like Phenotypes.

PubMed

Uva, Paolo; Cossu-Rocca, Paolo; Loi, Federica; Pira, Giovanna; Murgia, Luciano; Orrù, Sandra; Floris, Matteo; Muroni, Maria Rosaria; Sanges, Francesca; Carru, Ciriaco; Angius, Andrea; De Miglio, Maria Rosaria

2018-01-01

The clinical and genetic heterogeneity of Triple Negative Breast Cancer (TNBC) and the lack of unambiguous molecular targets contribute to the inadequacy of current therapeutic options for these variants. MicroRNAs (miRNA) are a class of small highly conserved regulatory endogenous non-coding RNA, which can alter the expression of genes encoding proteins and may play a role in the dysregulation of cellular pathways. Our goal was to improve the knowledge of the molecular pathogenesis of TNBC subgroups analyzing the miRNA expression profile, and to identify new prognostic and predictive biomarkers. We conducted a human miRNome analysis by TaqMan Low Density Array comparing different TNBC subtypes, defined by immunohistochemical basal markers EGFR and CK5/6. RT-qPCR confirmed differential expression of microRNAs. To inspect the function of the selected targets we perform Gene Ontology and KEGG enrichment analysis. We identified a single miRNA signature given by miR-135b expression level, which was strictly related to TNBC with basal-like phenotype. miR-135b target analysis revealed a role in the TGF-beta, WNT and ERBB pathways. A significant positive correlation was identified between neoplastic proliferative index and miR-135b expression. These findings confirm the oncogenic roles of miR-135b in the pathogenesis of TNBC expressing basal markers. A potential negative prognostic role of miR-135b overexpression might be related to the positive correlation with high proliferative index. Our study implies potential clinical applications: miR-135b could be a potential therapeutic target in basal-like TNBCs.

miRNA-135b Contributes to Triple Negative Breast Cancer Molecular Heterogeneity: Different Expression Profile in Basal-like Versus non-Basal-like Phenotypes

PubMed Central

Uva, Paolo; Cossu-Rocca, Paolo; Loi, Federica; Pira, Giovanna; Murgia, Luciano; Orrù, Sandra; Floris, Matteo; Muroni, Maria Rosaria; Sanges, Francesca; Carru, Ciriaco; Angius, Andrea; De Miglio, Maria Rosaria

2018-01-01

The clinical and genetic heterogeneity of Triple Negative Breast Cancer (TNBC) and the lack of unambiguous molecular targets contribute to the inadequacy of current therapeutic options for these variants. MicroRNAs (miRNA) are a class of small highly conserved regulatory endogenous non-coding RNA, which can alter the expression of genes encoding proteins and may play a role in the dysregulation of cellular pathways. Our goal was to improve the knowledge of the molecular pathogenesis of TNBC subgroups analyzing the miRNA expression profile, and to identify new prognostic and predictive biomarkers. We conducted a human miRNome analysis by TaqMan Low Density Array comparing different TNBC subtypes, defined by immunohistochemical basal markers EGFR and CK5/6. RT-qPCR confirmed differential expression of microRNAs. To inspect the function of the selected targets we perform Gene Ontology and KEGG enrichment analysis. We identified a single miRNA signature given by miR-135b expression level, which was strictly related to TNBC with basal-like phenotype. miR-135b target analysis revealed a role in the TGF-beta, WNT and ERBB pathways. A significant positive correlation was identified between neoplastic proliferative index and miR-135b expression. These findings confirm the oncogenic roles of miR-135b in the pathogenesis of TNBC expressing basal markers. A potential negative prognostic role of miR-135b overexpression might be related to the positive correlation with high proliferative index. Our study implies potential clinical applications: miR-135b could be a potential therapeutic target in basal-like TNBCs. PMID:29725243

A novel mutation of the beta myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy.

PubMed

Wang, Juan; Xu, Shi-Jie; Zhou, Hua; Wang, Li-Jie; Hu, Bo; Fang, Fang; Zhang, Xu-Min; Luo, Yi-Wei; He, Xiao-Yan; Zhuang, Shao-Wei; Li, Xin-Ming; Liu, Zhong-Ming; Hu, Da-Yi

2009-09-01

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder and shows high variability in genetic heterogeneity and phenotypic characteristics. The genetic etiology responsible for HCM in many individuals remains unclear. This instigation was sought to identify novel genetic determinants for familial hypertrophic cardiomyopathy. Six unrelated Chinese families with HCM were studied. For each of the 13 established HCM-susceptibility genes, 3 to 5 microsatellite markers were selected to perform genotyping and haplotype analysis. The linked genes were sequenced. Haplotype analyses on candidate genetic loci revealed cosegregation of the gene beta-myosin heavy chain (MYH7) with HCM in a single family. A novel double heterozygous missense mutation of Ala26Val plus Arg719Trp in MYH7 was subsequently identified by sequencing in this family and was associated with a severe phenotype of HCM. The novel double mutation of Ala26Val plus Arg719Trp in MYH7 identified in a Chinese family highlights the remarkable genetic heterogeneity of HCM, which provides important information for genetic counseling, accurate diagnosis, prognostic evaluation, and appropriate clinical management. Copyright 2009 Wiley Periodicals, Inc.

Antibodies in juvenile-onset myositis.

PubMed

Tansley, Sarah L

2016-11-01

Juvenile-onset myositis is a highly heterogeneous disease. Myositis-specific and associated autoantibodies provide a potential means of subdividing patients into clinically homogenous subgroups. Given the increasing availability of autoantibody testing, this review explores the phenotypes associated with different autoantibodies in juvenile-onset myositis and the potential clinical utility of autoantibody testing. Autoantibodies can be identified in 60-70% of children with myositis and the recent discovery of novel myositis-associated autoantibodies in adult patients suggests this may increase in the near future. Detailed phenotype descriptions are now known for several autoantibodies commonly identified in juvenile-onset disease. Whilst there is insufficient evidence to recommend a differential treatment approach based on autoantibody status, it is becoming increasingly clear that some autoantibody subgroups are often treatment resistant and may benefit from a more aggressive approach. The validation of nonspecialised methods for myositis-specific autoantibody detection should lead to more widely available testing. In juvenile-onset disease, this will provide detailed prognostic information and in the future may also influence approach.

Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades.

PubMed

Li, Ningning; Zhang, Ying; Sidlauskas, Kastytis; Ellis, Matthew; Evans, Ian; Frankel, Paul; Lau, Joanne; El-Hassan, Tedani; Guglielmi, Loredana; Broni, Jessica; Richard-Loendt, Angela; Brandner, Sebastian

2018-05-03

To identify biomarkers for glioma growth, invasion and progression, we used a candidate gene approach in mouse models with two complementary brain tumour phenotypes, developing either slow-growing, diffusely infiltrating gliomas or highly proliferative, non-invasive primitive neural tumours. In a microRNA screen we first identified microRNA-449a as most significantly differentially expressed between these two tumour types. miR-449a has a target dependent effect, inhibiting cell growth and migration by downregulation of CCND1 and suppressing neural phenotypes by inhibition of G protein coupled-receptor (GPR) 158. GPR158 promotes glioma stem cell differentiation and induces apoptosis and is highest expressed in the cerebral cortex and in oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma, IDH wild-type glioblastoma. The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggests a possible role of GPR158 as prognostic biomarker in human gliomas.

Imaging Intratumor Heterogeneity: Role in Therapy Response, Resistance, and Clinical Outcome

PubMed Central

O’Connor, James P.B.; Rose, Chris J.; Waterton, John C.; Carano, Richard A.D.; Parker, Geoff J.M.; Jackson, Alan

2014-01-01

Tumors exhibit genomic and phenotypic heterogeneity which has prognostic significance and may influence response to therapy. Imaging can quantify the spatial variation in architecture and function of individual tumors through quantifying basic biophysical parameters such as density or MRI signal relaxation rate; through measurements of blood flow, hypoxia, metabolism, cell death and other phenotypic features; and through mapping the spatial distribution of biochemical pathways and cell signaling networks. These methods can establish whether one tumor is more or less heterogeneous than another and can identify sub-regions with differing biology. In this article we review the image analysis methods currently used to quantify spatial heterogeneity within tumors. We discuss how analysis of intratumor heterogeneity can provide benefit over more simple biomarkers such as tumor size and average function. We consider how imaging methods can be integrated with genomic and pathology data, rather than be developed in isolation. Finally, we identify the challenges that must be overcome before measurements of intratumoral heterogeneity can be used routinely to guide patient care. PMID:25421725

Efficiency and prognosis of whole brain irradiation combined with precise radiotherapy on triple-negative breast cancer.

PubMed

Wu, Xinhong; Luo, Bo; Wei, Shaozhong; Luo, Yan; Feng, Yaojun; Xu, Juan; Wei, Wei

2013-11-01

To investigate the treatment efficiency of whole brain irradiation combined with precise radiotherapy on triple-negative (TN) phenotype breast cancer patients with brain metastases and their survival times. A total of 112 metastatic breast cancer patients treated with whole brain irradiation and intensity modulated radiotherapy (IMRT) or 3D conformal radiotherapy (3DCRT) were analyzed. Thirty-seven patients were of TN phenotype. Objective response rates were compared. Survival times were estimated by using the Kaplan-Meier method. Log-rank test was used to compare the survival time difference between the TN and non-TN groups. Potential prognostic factors were determined by using a Cox proportional hazard regression model. The efficiency of radiotherapy treatment on TN and non-TN phenotypes was 96.2% and 97%, respectively. TN phenotype was associated with worse survival times than non-TN phenotype after radiotherapy (6.9 months vs. 17 months) (P < 0.01). On multivariate analysis, good prognosis was associated with non-TN status, lower graded prognosis assessment class, and nonexistence of active extracranial metastases. After whole brain irradiation followed by IMRT or 3DCRT treatment, TN phenotype breast cancer patients with intracranial metastasis had high objective response rates but shorter survival time. With respect to survival in breast cancer patients with intracranial metastasis, the TN phenotype represents a significant adverse prognostic factor.

Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis

PubMed Central

Pemov, Alexander; Sung, Heejong; Hyland, Paula L.; Sloan, Jennifer L.; Ruppert, Sarah L.; Baldwin, Andrea M.; Boland, Joseph F.; Bass, Sara E.; Lee, Hyo Jung; Jones, Kristine M.; Zhang, Xijun; Mullikin, James C.; Widemann, Brigitte C.; Wilson, Alexander F.; Stewart, Douglas R.

2014-01-01

Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count. PMID:25329635

Two microRNA signatures for malignancy and immune infiltration predict overall survival in advanced epithelial ovarian cancer.

PubMed

Korsunsky, Ilya; Parameswaran, Janaki; Shapira, Iuliana; Lovecchio, John; Menzin, Andrew; Whyte, Jill; Dos Santos, Lisa; Liang, Sharon; Bhuiya, Tawfiqul; Keogh, Mary; Khalili, Houman; Pond, Cassandra; Liew, Anthony; Shih, Andrew; Gregersen, Peter K; Lee, Annette T

2017-10-01

MicroRNAs have been established as key regulators of tumor gene expression and as prime biomarker candidates for clinical phenotypes in epithelial ovarian cancer (EOC). We analyzed the coexpression and regulatory structure of microRNAs and their co-localized gene targets in primary tumor tissue of 20 patients with advanced EOC in order to construct a regulatory signature for clinical prognosis. We performed an integrative analysis to identify two prognostic microRNA/mRNA coexpression modules, each enriched for consistent biological functions. One module, enriched for malignancy-related functions, was found to be upregulated in malignant versus benign samples. The second module, enriched for immune-related functions, was strongly correlated with imputed intratumoral immune infiltrates of T cells, natural killer cells, cytotoxic lymphocytes, and macrophages. We validated the prognostic relevance of the immunological module microRNAs in the publicly available The Cancer Genome Atlas data set. These findings provide novel functional roles for microRNAs in the progression of advanced EOC and possible prognostic signatures for survival. © American Federation for Medical Research (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Neuroblastoma in children: Update on clinicopathologic and genetic prognostic factors.

PubMed

Ahmed, Atif A; Zhang, Lei; Reddivalla, Naresh; Hetherington, Maxine

2017-04-01

Neuroblastoma is the most common extracranial solid tumor in childhood accounting for 8-10% of all childhood malignancies. The tumor is characterized by a spectrum of histopathologic features and a heterogeneous clinical phenotype. Modern multimodality therapy results in variable clinical response ranging from cure in localized tumors to limited response in aggressive metastatic disease. Accurate clinical staging and risk assessment based on clinical, surgical, biologic and pathologic criteria are of pivotal importance in assigning prognosis and planning effective treatment approaches. Numerous studies have analyzed the presence of several clinicopathologic and biologic factors in association with the patient's prognosis and outcome. Although patient's age, tumor stage, histopathologic classification, and MYCN amplification are the most commonly validated prognostic markers, several new gene mutations have been identified in sporadic and familial neuroblastoma cases that show association with an adverse outcome. Novel molecular studies have also added data on chromosomal segmental aberrations in MYCN nonamplified tumors. In this review, we provide an updated summary of the clinical, serologic and genetic prognostic indicators in neuroblastoma including classic factors that have consistently played a role in risk stratification of patients as well as newly discovered biomarkers that may show a potential significance in patients' management.

Hemochromatosis Enhances Tumor Progression via Upregulation of Intracellular Iron in Head and Neck Cancer

PubMed Central

Lenarduzzi, Michelle; Hui, Angela B. Y.; Yue, Shijun; Ito, Emma; Shi, Wei; Williams, Justin; Bruce, Jeff; Sakemura-Nakatsugawa, Noriko; Xu, Wei; Schimmer, Aaron; Liu, Fei-Fei

2013-01-01

Introduction Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), outcomes have not significantly improved; highlighting the importance of identifying novel therapeutic approaches to target this disease. To address this challenge, we proceeded to evaluate the role of iron in HNSCC. Experimental Design Expression levels of iron-related genes were evaluated in HNSCC cell lines using quantitative RT-PCR. Cellular phenotypic effects were assessed using viability (MTS), clonogenic survival, BrdU, and tumor formation assays. The prognostic significance of iron-related proteins was determined using immunohistochemistry. Results In a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. In vitro knockdown of HFE in HNSCC cell lines significantly decreased hepcidin (HAMP) expression and intracellular iron level. This in turn, resulted in a significant decrease in HNSCC cell viability, clonogenicity, DNA synthesis, and Wnt signalling. These cellular changes were reversed by re-introducing iron back into HNSCC cells after HFE knockdown, indicating that iron was mediating this phenotype. Concordantly, treating HNSCC cells with an iron chelator, ciclopirox olamine (CPX), significantly reduced viability and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression. Conclusions Our data identify HFE as potentially novel prognostic marker in HNSCC that promotes tumour progression via HAMP and elevated intracellular iron levels, leading to increased cellular proliferation and tumour formation. Hence, these findings suggest that iron chelators might have a therapeutic role in HNSCC management. PMID:23991213

Cluster analysis and prediction of treatment outcomes for chronic rhinosinusitis.

PubMed

Soler, Zachary M; Hyer, J Madison; Rudmik, Luke; Ramakrishnan, Viswanathan; Smith, Timothy L; Schlosser, Rodney J

2016-04-01

Current clinical classifications of chronic rhinosinusitis (CRS) have weak prognostic utility regarding treatment outcomes. Simplified discriminant analysis based on unsupervised clustering has identified novel phenotypic subgroups of CRS, but prognostic utility is unknown. We sought to determine whether discriminant analysis allows prognostication in patients choosing surgery versus continued medical management. A multi-institutional prospective study of patients with CRS in whom initial medical therapy failed who then self-selected continued medical management or surgical treatment was used to separate patients into 5 clusters based on a previously described discriminant analysis using total Sino-Nasal Outcome Test-22 (SNOT-22) score, age, and missed productivity. Patients completed the SNOT-22 at baseline and for 18 months of follow-up. Baseline demographic and objective measures included olfactory testing, computed tomography, and endoscopy scoring. SNOT-22 outcomes for surgical versus continued medical treatment were compared across clusters. Data were available on 690 patients. Baseline differences in demographics, comorbidities, objective disease measures, and patient-reported outcomes were similar to previous clustering reports. Three of 5 clusters identified by means of discriminant analysis had improved SNOT-22 outcomes with surgical intervention when compared with continued medical management (surgery was a mean of 21.2 points better across these 3 clusters at 6 months, P < .05). These differences were sustained at 18 months of follow-up. Two of 5 clusters had similar outcomes when comparing surgery with continued medical management. A simplified discriminant analysis based on 3 common clinical variables is able to cluster patients and provide prognostic information regarding surgical treatment versus continued medical management in patients with CRS. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

TEPAPA: a novel in silico feature learning pipeline for mining prognostic and associative factors from text-based electronic medical records.

PubMed

Lin, Frank Po-Yen; Pokorny, Adrian; Teng, Christina; Epstein, Richard J

2017-07-31

Vast amounts of clinically relevant text-based variables lie undiscovered and unexploited in electronic medical records (EMR). To exploit this untapped resource, and thus facilitate the discovery of informative covariates from unstructured clinical narratives, we have built a novel computational pipeline termed Text-based Exploratory Pattern Analyser for Prognosticator and Associator discovery (TEPAPA). This pipeline combines semantic-free natural language processing (NLP), regular expression induction, and statistical association testing to identify conserved text patterns associated with outcome variables of clinical interest. When we applied TEPAPA to a cohort of head and neck squamous cell carcinoma patients, plausible concepts known to be correlated with human papilloma virus (HPV) status were identified from the EMR text, including site of primary disease, tumour stage, pathologic characteristics, and treatment modalities. Similarly, correlates of other variables (including gender, nodal status, recurrent disease, smoking and alcohol status) were also reliably recovered. Using highly-associated patterns as covariates, a patient's HPV status was classifiable using a bootstrap analysis with a mean area under the ROC curve of 0.861, suggesting its predictive utility in supporting EMR-based phenotyping tasks. These data support using this integrative approach to efficiently identify disease-associated factors from unstructured EMR narratives, and thus to efficiently generate testable hypotheses.

The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry.

PubMed

Roston, Thomas M; Yuchi, Zhiguang; Kannankeril, Prince J; Hathaway, Julie; Vinocur, Jeffrey M; Etheridge, Susan P; Potts, James E; Maginot, Kathleen R; Salerno, Jack C; Cohen, Mitchell I; Hamilton, Robert M; Pflaumer, Andreas; Mohammed, Saira; Kimlicka, Lynn; Kanter, Ronald J; LaPage, Martin J; Collins, Kathryn K; Gebauer, Roman A; Temple, Joel D; Batra, Anjan S; Erickson, Christopher; Miszczak-Knecht, Maria; Kubuš, Peter; Bar-Cohen, Yaniv; Kantoch, Michal; Thomas, Vincent C; Hessling, Gabriele; Anderson, Chris; Young, Ming-Lon; Choi, Sally H J; Cabrera Ortega, Michel; Lau, Yung R; Johnsrude, Christopher L; Fournier, Anne; Van Petegem, Filip; Sanatani, Shubhayan

2018-03-01

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.

DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia.

PubMed

Borssén, Magnus; Haider, Zahra; Landfors, Mattias; Norén-Nyström, Ulrika; Schmiegelow, Kjeld; Åsberg, Ann E; Kanerva, Jukka; Madsen, Hans O; Marquart, Hanne; Heyman, Mats; Hultdin, Magnus; Roos, Göran; Forestier, Erik; Degerman, Sofie

2016-07-01

Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y ) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD ≥0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making. © 2016 Wiley Periodicals, Inc.

Identifying and Assessing Interesting Subgroups in a Heterogeneous Population.

PubMed

Lee, Woojoo; Alexeyenko, Andrey; Pernemalm, Maria; Guegan, Justine; Dessen, Philippe; Lazar, Vladimir; Lehtiö, Janne; Pawitan, Yudi

2015-01-01

Biological heterogeneity is common in many diseases and it is often the reason for therapeutic failures. Thus, there is great interest in classifying a disease into subtypes that have clinical significance in terms of prognosis or therapy response. One of the most popular methods to uncover unrecognized subtypes is cluster analysis. However, classical clustering methods such as k-means clustering or hierarchical clustering are not guaranteed to produce clinically interesting subtypes. This could be because the main statistical variability--the basis of cluster generation--is dominated by genes not associated with the clinical phenotype of interest. Furthermore, a strong prognostic factor might be relevant for a certain subgroup but not for the whole population; thus an analysis of the whole sample may not reveal this prognostic factor. To address these problems we investigate methods to identify and assess clinically interesting subgroups in a heterogeneous population. The identification step uses a clustering algorithm and to assess significance we use a false discovery rate- (FDR-) based measure. Under the heterogeneity condition the standard FDR estimate is shown to overestimate the true FDR value, but this is remedied by an improved FDR estimation procedure. As illustrations, two real data examples from gene expression studies of lung cancer are provided.

Prognostic biomarkers in osteoarthritis

PubMed Central

Attur, Mukundan; Krasnokutsky-Samuels, Svetlana; Samuels, Jonathan; Abramson, Steven B.

2013-01-01

Purpose of review Identification of patients at risk for incident disease or disease progression in osteoarthritis remains challenging, as radiography is an insensitive reflection of molecular changes that presage cartilage and bone abnormalities. Thus there is a widely appreciated need for biochemical and imaging biomarkers. We describe recent developments with such biomarkers to identify osteoarthritis patients who are at risk for disease progression. Recent findings The biochemical markers currently under evaluation include anabolic, catabolic, and inflammatory molecules representing diverse biological pathways. A few promising cartilage and bone degradation and synthesis biomarkers are in various stages of development, awaiting further validation in larger populations. A number of studies have shown elevated expression levels of inflammatory biomarkers, both locally (synovial fluid) and systemically (serum and plasma). These chemical biomarkers are under evaluation in combination with imaging biomarkers to predict early onset and the burden of disease. Summary Prognostic biomarkers may be used in clinical knee osteoarthritis to identify subgroups in whom the disease progresses at different rates. This could facilitate our understanding of the pathogenesis and allow us to differentiate phenotypes within a heterogeneous knee osteoarthritis population. Ultimately, such findings may help facilitate the development of disease-modifying osteoarthritis drugs (DMOADs). PMID:23169101

Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype

PubMed Central

Wei, Caimiao; Gould, Rebekah; Yu, Xian; Zhang, Ya; Liu, Mei; Walls, Andrew; Bousamra, Alex; Ramineni, Maheshwari; Sinn, Bruno; Hunt, Kelly; Buchholz, Thomas A.; Valero, Vicente; Buzdar, Aman U.; Yang, Wei; Brewster, Abenaa M.; Moulder, Stacy; Pusztai, Lajos; Hatzis, Christos; Hortobagyi, Gabriel N.

2017-01-01

Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)–targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor–negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor–negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated. PMID:28135148

Latent topic discovery of clinical concepts from hospital discharge summaries of a heterogeneous patient cohort.

PubMed

Lehman, Li-Wei; Long, William; Saeed, Mohammed; Mark, Roger

2014-01-01

Patients in critical care often exhibit complex disease patterns. A fundamental challenge in clinical research is to identify clinical features that may be characteristic of adverse patient outcomes. In this work, we propose a data-driven approach for phenotype discovery of patients in critical care. We used Hierarchical Dirichlet Process (HDP) as a non-parametric topic modeling technique to automatically discover the latent "topic" structure of diseases, symptoms, and findings documented in hospital discharge summaries. We show that the latent topic structure can be used to reveal phenotypic patterns of diseases and symptoms shared across subgroups of a patient cohort, and may contain prognostic value in stratifying patients' post hospital discharge mortality risks. Using discharge summaries of a large patient cohort from the MIMIC II database, we evaluate the clinical utility of the discovered topic structure in identifying patients who are at high risk of mortality within one year post hospital discharge. We demonstrate that the learned topic structure has statistically significant associations with mortality post hospital discharge, and may provide valuable insights in defining new feature sets for predicting patient outcomes.

Imaging intratumor heterogeneity: role in therapy response, resistance, and clinical outcome.

PubMed

O'Connor, James P B; Rose, Chris J; Waterton, John C; Carano, Richard A D; Parker, Geoff J M; Jackson, Alan

2015-01-15

Tumors exhibit genomic and phenotypic heterogeneity, which has prognostic significance and may influence response to therapy. Imaging can quantify the spatial variation in architecture and function of individual tumors through quantifying basic biophysical parameters such as CT density or MRI signal relaxation rate; through measurements of blood flow, hypoxia, metabolism, cell death, and other phenotypic features; and through mapping the spatial distribution of biochemical pathways and cell signaling networks using PET, MRI, and other emerging molecular imaging techniques. These methods can establish whether one tumor is more or less heterogeneous than another and can identify subregions with differing biology. In this article, we review the image analysis methods currently used to quantify spatial heterogeneity within tumors. We discuss how analysis of intratumor heterogeneity can provide benefit over more simple biomarkers such as tumor size and average function. We consider how imaging methods can be integrated with genomic and pathology data, instead of being developed in isolation. Finally, we identify the challenges that must be overcome before measurements of intratumoral heterogeneity can be used routinely to guide patient care. ©2014 American Association for Cancer Research.

Prognostic factor analysis of circulating tumor cells in peripheral blood of patients with peritoneal carcinomatosis of colon cancer origin treated with cytoreductive surgery plus an intraoperative hyperthermic intraperitoneal chemotherapy procedure (CRS + HIPEC).

PubMed

Melero, Juan Torres; Ortega, Francisco G; Gonzalez, Alvaro Morales; Carmona-Saez, Pedro; Garcia Puche, Jose L; Sugarbaker, Paul H; Delgado, Miguel; Lorente, José A; Serrano, María José

2016-03-01

Complete cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has changed the therapeutic landscape, improving overall survival in patients with peritoneal carcinomatosis with a colonic origin. The main limitation of this aggressive locoregional procedure, however, is extra-abdominal or distant spread. The objective of this study was to identify the prognostic value of circulating tumor cells (CTCs) in patients with peritoneal carcinomatosis of colonic origin undergoing CRS + HIPEC. Fourteen patients diagnosed with peritoneal carcinomatosis from colon cancer and suitable for potentially curative treatment with CRS + HIPEC were included in this study. CTCs were isolated from the peripheral blood by immunomagnetic techniques by the use of a multi-cytokeratin-specific antibody and detected via immunocytochemical methods. The phenotypic characterization of EGFR on CTCs was analyzed by immunofluorescence. At baseline, 50% of the patients were positive for CTCs, with a mean value of 5.5 CTCs per 10 mL of peripheral blood. After surgery, 28.57% of the patients presented CTCs, with a mean value of 6.75 CTCs per 10 mL. A positive correlation was found between the presence of CTC-negative, epidermal growth factor receptor-positive at baseline and the patients who had symptoms of intestinal obstruction (21.4%). In addition, the presence of CTCs identified patients with distant dissemination and was also significantly correlated with progression-free survival (P = .0024). The detection and characterization of CTCs are good prognostic and predictive markers in patients with peritoneal carcinomatosis resulting from colon cancer. These analyses could be used as a new tool to identify subpopulations of patients who could benefit from CRS + HIPEC treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical Implications of Cluster Analysis-Based Classification of Acute Decompensated Heart Failure and Correlation with Bedside Hemodynamic Profiles.

PubMed

Ahmad, Tariq; Desai, Nihar; Wilson, Francis; Schulte, Phillip; Dunning, Allison; Jacoby, Daniel; Allen, Larry; Fiuzat, Mona; Rogers, Joseph; Felker, G Michael; O'Connor, Christopher; Patel, Chetan B

2016-01-01

Classification of acute decompensated heart failure (ADHF) is based on subjective criteria that crudely capture disease heterogeneity. Improved phenotyping of the syndrome may help improve therapeutic strategies. To derive cluster analysis-based groupings for patients hospitalized with ADHF, and compare their prognostic performance to hemodynamic classifications derived at the bedside. We performed a cluster analysis on baseline clinical variables and PAC measurements of 172 ADHF patients from the ESCAPE trial. Employing regression techniques, we examined associations between clusters and clinically determined hemodynamic profiles (warm/cold/wet/dry). We assessed association with clinical outcomes using Cox proportional hazards models. Likelihood ratio tests were used to compare the prognostic value of cluster data to that of hemodynamic data. We identified four advanced HF clusters: 1) male Caucasians with ischemic cardiomyopathy, multiple comorbidities, lowest B-type natriuretic peptide (BNP) levels; 2) females with non-ischemic cardiomyopathy, few comorbidities, most favorable hemodynamics; 3) young African American males with non-ischemic cardiomyopathy, most adverse hemodynamics, advanced disease; and 4) older Caucasians with ischemic cardiomyopathy, concomitant renal insufficiency, highest BNP levels. There was no association between clusters and bedside-derived hemodynamic profiles (p = 0.70). For all adverse clinical outcomes, Cluster 4 had the highest risk, and Cluster 2, the lowest. Compared to Cluster 4, Clusters 1-3 had 45-70% lower risk of all-cause mortality. Clusters were significantly associated with clinical outcomes, whereas hemodynamic profiles were not. By clustering patients with similar objective variables, we identified four clinically relevant phenotypes of ADHF patients, with no discernable relationship to hemodynamic profiles, but distinct associations with adverse outcomes. Our analysis suggests that ADHF classification using simultaneous considerations of etiology, comorbid conditions, and biomarker levels, may be superior to bedside classifications.

Meta-analysis of the prognostic value of CpG island methylator phenotype in gastric cancer.

PubMed

Powell, A G M T; Soul, S; Christian, A; Lewis, W G

2018-01-01

CpG island methylator phenotype (CIMP) has been identified as a distinct molecular subtype of gastric cancer, yet associations with survival are conflicting. A meta-analysis was performed to estimate the prognostic significance of CIMP. Embase, MEDLINE, PubMed, PubMed Central and Cochrane databases were searched systematically for studies related to the association between CIMP and survival in patients undergoing potentially curative resection for gastric cancer. A total of 918 patients from ten studies were included, and the median proportion of tumours with CIMP-high (CIMP-H) status was 40·9 (range 4·8-63) per cent. Gene panels for assessing CIMP status varied between the studies. Pooled analysis suggested that specimens exhibiting CIMP-H were associated with poorer 5-year survival (odds ratio (OR) for death 1·48, 95 per cent c.i. 1·10 to 1·99; P = 0·009). Significant heterogeneity was observed between studies (I 2 = 88 per cent, P < 0·001). Subgroup analysis according to whether studies showed a tendency towards poor (5 studies) or improved (5) outcomes for patients with CIMP-H tumours, revealed that CIMP-H was associated with both poor (OR for death 8·15, 4·65 to 14·28, P < 0·001; heterogeneity I 2 = 52 per cent, P = 0·08) and improved (OR 0·42, 0·27 to 0·65; P < 0·001, heterogeneity I 2 = 0 per cent, P = 0·960) survival. There was heterogeneity in the gene panels used to identify CIMP, which may explain the survival differences. © 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.

Small bowel carcinomas in celiac or Crohn's disease: distinctive histophenotypic, molecular and histogenetic patterns.

PubMed

Vanoli, Alessandro; Di Sabatino, Antonio; Martino, Michele; Klersy, Catherine; Grillo, Federica; Mescoli, Claudia; Nesi, Gabriella; Volta, Umberto; Fornino, Daniele; Luinetti, Ombretta; Fociani, Paolo; Villanacci, Vincenzo; D'Armiento, Francesco P; Cannizzaro, Renato; Latella, Giovanni; Ciacci, Carolina; Biancone, Livia; Paulli, Marco; Sessa, Fausto; Rugge, Massimo; Fiocca, Roberto; Corazza, Gino R; Solcia, Enrico

2017-10-01

Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune-inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (β-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease-associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage- and microsatellite instability/tumor-infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non-intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear β-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat β-catenin-positive dysplasia, and of Crohn's disease-associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis.

On the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review.

PubMed

Zollino, Marcella; Murdolo, Marina; Marangi, Giuseppe; Pecile, Vanna; Galasso, Cinzia; Mazzanti, Laura; Neri, Giovanni

2008-11-15

Based on genotype-phenotype correlation analysis of 80 Wolf-Hirschhorn syndrome (WHS) patients, as well as on review of relevant literature, we add further insights to the following aspects of WHS: (1) clinical delineation and phenotypic categories; (2) characterization of the basic genomic defect, mechanisms of origin and familiarity; (3) identification of prognostic factors for mental retardation; (4) chromosome mapping of the distinctive clinical signs, in an effort to identify pathogenic genes. Clinically, we consider that minimal diagnostic criteria for WHS, defining a "core" phenotype, are typical facial appearance, mental retardation, growth delay and seizures (or EEG anomalies). Three different categories of the WHS phenotype were defined, generally correlating with the extent of the 4p deletion. The first one comprises a small deletion not exceeding 3.5 Mb, that is usually associated with a mild phenotype, lacking major malformations. This category is likely under-diagnosed. The second and by far the more frequent category is identified by large deletions, averaging between 5 and 18 Mb, and causes the widely recognizable WHS phenotype. The third clinical category results from a very large deletion exceeding 22-25 Mb causing a severe phenotype, that can hardly be defined as typical WHS. Genetically, de novo chromosome abnormalities in WHS include pure deletions but also complex rearrangements, mainly unbalanced translocations. With the exception of t(4p;8p), WHS-associated chromosome abnormalities are neither mediated by segmental duplications, nor associated with a parental inversion polymorphism on 4p16.3. Factors involved in prediction of prognosis include the extent of the deletion, the occurrence of complex chromosome anomalies, and the severity of seizures. We found that the core phenotype maps within the terminal 1.9 Mb region of chromosome 4p. Therefore, WHSCR-2 should be considered the critical region for this condition. We also confirmed that the pathogenesis of WHS is multigenic. Specific and independent chromosome regions were characterized for growth delay and seizures, as well as for the additional clinical signs that characterize this condition. With the exception of parental balanced translocations, familial recurrence is uncommon.

SU-F-R-52: A Comparison of the Performance of Radiomic Features From Free Breathing and 4DCT Scans in Predicting Disease Recurrence in Lung Cancer SBRT Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huynh, E; Coroller, T; Narayan, V

Purpose: There is a clinical need to identify patients who are at highest risk of recurrence after being treated with stereotactic body radiation therapy (SBRT). Radiomics offers a non-invasive approach by extracting quantitative features from medical images based on tumor phenotype that is predictive of an outcome. Lung cancer patients treated with SBRT routinely undergo free breathing (FB image) and 4DCT (average intensity projection (AIP) image) scans for treatment planning to account for organ motion. The aim of the current study is to evaluate and compare the prognostic performance of radiomic features extracted from FB and AIP images in lungmore » cancer patients treated with SBRT to identify which image type would generate an optimal predictive model for recurrence. Methods: FB and AIP images of 113 Stage I-II NSCLC patients treated with SBRT were analysed. The prognostic performance of radiomic features for distant metastasis (DM) was evaluated by their concordance index (CI). Radiomic features were compared with conventional imaging metrics (e.g. diameter). All p-values were corrected for multiple testing using the false discovery rate. Results: All patients received SBRT and 20.4% of patients developed DM. From each image type (FB or AIP), nineteen radiomic features were selected based on stability and variance. Both image types had five common and fourteen different radiomic features. One FB (CI=0.70) and five AIP (CI range=0.65–0.68) radiomic features were significantly prognostic for DM (p<0.05). None of the conventional features derived from FB images (range CI=0.60–0.61) were significant but all AIP conventional features were (range CI=0.64–0.66). Conclusion: Features extracted from different types of CT scans have varying prognostic performances. AIP images contain more prognostic radiomic features for DM than FB images. These methods can provide personalized medicine approaches at low cost, as FB and AIP data are readily available within a large number of radiation oncology departments. R.M. had consulting interest with Amgen (ended in 2015).« less

Potential of DNA methylation in rectal cancer as diagnostic and prognostic biomarkers

PubMed Central

Exner, Ruth; Pulverer, Walter; Diem, Martina; Spaller, Lisa; Woltering, Laura; Schreiber, Martin; Wolf, Brigitte; Sonntagbauer, Markus; Schröder, Fabian; Stift, Judith; Wrba, Fritz; Bergmann, Michael; Weinhäusel, Andreas; Egger, Gerda

2015-01-01

Background: Aberrant DNA methylation is more prominent in proximal compared with distal colorectal cancers. Although a number of methylation markers were identified for colon cancer, yet few are available for rectal cancer. Methods: DNA methylation differences were assessed by a targeted DNA microarray for 360 marker candidates between 22 fresh frozen rectal tumour samples and 8 controls and validated by microfluidic high-throughput and methylation-sensitive qPCR in fresh frozen and formalin-fixed paraffin-embedded (FFPE) samples, respectively. The CpG island methylator phenotype (CIMP) was assessed by MethyLight in FFPE material from 78 patients with pT2 and pT3 rectal adenocarcinoma. Results: We identified and confirmed two novel three-gene signatures in fresh frozen samples that can distinguish tumours from adjacent tissue as well as from blood with a high sensitivity and specificity of up to 1 and an AUC of 1. In addition, methylation of individual CIMP markers was associated with specific clinical parameters such as tumour stage, therapy or patients' age. Methylation of CDKN2A was a negative prognostic factor for overall survival of patients. Conclusions: The newly defined methylation markers will be suitable for early disease detection and monitoring of rectal cancer. PMID:26335606

Matrix-regulated integrin αvβ5 maintains α5β1-dependent desmoplastic traits prognostic of neoplastic recurrence

PubMed Central

Franco-Barraza, Janusz; Francescone, Ralph; Luong, Tiffany; Shah, Neelima; Madhani, Raj; Cukierman, Gil; Dulaimi, Essel; Devarajan, Karthik; Egleston, Brian L; Nicolas, Emmanuelle; Katherine Alpaugh, R; Malik, Ruchi; Uzzo, Robert G; Hoffman, John P; Golemis, Erica A; Cukierman, Edna

2017-01-01

Desmoplasia, a fibrotic mass including cancer-associated fibroblasts (CAFs) and self-sustaining extracellular matrix (D-ECM), is a puzzling feature of pancreatic ductal adenocarcinoma (PDACs). Conflicting studies have identified tumor-restricting and tumor-promoting roles of PDAC-associated desmoplasia, suggesting that individual CAF/D-ECM protein constituents have distinguishable tumorigenic and tumor-repressive functions. Using 3D culture of normal pancreatic versus PDAC-associated human fibroblasts, we identified a CAF/D-ECM phenotype that correlates with improved patient outcomes, and that includes CAFs enriched in plasma membrane-localized, active α5β1-integrin. Mechanistically, we established that TGFβ is required for D-ECM production but dispensable for D-ECM-induced naïve fibroblast-to-CAF activation, which depends on αvβ5-integrin redistribution of pFAK-independent active α5β1-integrin to assorted endosomes. Importantly, the development of a simultaneous multi-channel immunofluorescence approach and new algorithms for computational batch-analysis and their application to a human PDAC panel, indicated that stromal localization and levels of active SMAD2/3 and α5β1-integrin distinguish patient-protective from patient-detrimental desmoplasia and foretell tumor recurrences, suggesting a useful new prognostic tool. DOI: http://dx.doi.org/10.7554/eLife.20600.001 PMID:28139197

Cooperative genomic alteration network reveals molecular classification across 12 major cancer types

PubMed Central

Zhang, Hongyi; Deng, Yulan; Zhang, Yong; Ping, Yanyan; Zhao, Hongying; Pang, Lin; Zhang, Xinxin; Wang, Li; Xu, Chaohan; Xiao, Yun; Li, Xia

2017-01-01

The accumulation of somatic genomic alterations that enables cells to gradually acquire growth advantage contributes to tumor development. This has the important implication of the widespread existence of cooperative genomic alterations in the accumulation process. Here, we proposed a computational method HCOC that simultaneously consider genetic context and downstream functional effects on cancer hallmarks to uncover somatic cooperative events in human cancers. Applying our method to 12 TCGA cancer types, we totally identified 1199 cooperative events with high heterogeneity across human cancers, and then constructed a pan-cancer cooperative alteration network. These cooperative events are associated with genomic alterations of some high-confident cancer drivers, and can trigger the dysfunction of hallmark associated pathways in a co-defect way rather than single alterations. We found that these cooperative events can be used to produce a prognostic classification that can provide complementary information with tissue-of-origin. In a further case study of glioblastoma, using 23 cooperative events identified, we stratified patients into molecularly relevant subtypes with a prognostic significance independent of the Glioma-CpG Island Methylator Phenotype (GCIMP). In summary, our method can be effectively used to discover cancer-driving cooperative events that can be valuable clinical markers for patient stratification. PMID:27899621

Identifying and Assessing Interesting Subgroups in a Heterogeneous Population

PubMed Central

Lee, Woojoo; Alexeyenko, Andrey; Pernemalm, Maria; Guegan, Justine; Dessen, Philippe; Lazar, Vladimir; Lehtiö, Janne; Pawitan, Yudi

2015-01-01

Biological heterogeneity is common in many diseases and it is often the reason for therapeutic failures. Thus, there is great interest in classifying a disease into subtypes that have clinical significance in terms of prognosis or therapy response. One of the most popular methods to uncover unrecognized subtypes is cluster analysis. However, classical clustering methods such as k-means clustering or hierarchical clustering are not guaranteed to produce clinically interesting subtypes. This could be because the main statistical variability—the basis of cluster generation—is dominated by genes not associated with the clinical phenotype of interest. Furthermore, a strong prognostic factor might be relevant for a certain subgroup but not for the whole population; thus an analysis of the whole sample may not reveal this prognostic factor. To address these problems we investigate methods to identify and assess clinically interesting subgroups in a heterogeneous population. The identification step uses a clustering algorithm and to assess significance we use a false discovery rate- (FDR-) based measure. Under the heterogeneity condition the standard FDR estimate is shown to overestimate the true FDR value, but this is remedied by an improved FDR estimation procedure. As illustrations, two real data examples from gene expression studies of lung cancer are provided. PMID:26339613

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bunge, S.; Steglich, C.; Kleijer, W.J.

Mucopolysaccharidosis type I (MPS I) is caused by alpha-L-iduronidase (IDUA) deficiency. Clinical severity ranges from mild (Scheie) and intermediate (Hurler/Scheie) to severe (Hurler) forms. We investigated 70 patients with various MPS I phenotypes for mutations of the IDUA gene. 28 different mutations on 93% of mutant alleles, defining 90% of the genotypes were characterized. The two common missense mutations Q70X and W402X were found on, respectively, 31% and 28% of mutant alleles. However, Q70X is much more frequent in Scandinavia (64%) than in other European countries (16%). L218P (4.3%) and A327P (6.4%) were also identified in several patients, while allmore » other mutations were found on only one or two alleles each. Of the 11 novel mutations identified in this study, G51D, L218P, D315Y, A327P, R489P, E404X, and R621X were associated with severe phenotypes. Eleven different small deletions and insertions were detected (134del12, 964delC, 1132del6, 1782del11, 1995del11, {Delta}D444/445, 252insC, 396insAC, 682insAC, 974ins12, and 1277ins9), most of them causing severe MPS I. Two novel Hurler/Scheie (M504T and W626R) and two novel Scheie point mutations (R89W and R383H) were also identified. Characterization of the primary genetic defect and establishing genotype/phenotype correlation is important for prognostic predictions, evaluation of therapeutic success, and prenatal diagnosis.« less

A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis

PubMed Central

Lucarelli, Marco; Bruno, Sabina Maria; Pierandrei, Silvia; Ferraguti, Giampiero; Stamato, Antonella; Narzi, Fabiana; Amato, Annalisa; Cimino, Giuseppe; Bertasi, Serenella; Quattrucci, Serena; Strom, Roberto

2015-01-01

Cystic fibrosis (CF) is a monogenic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genotype–phenotype relationship in this disease is still unclear, and diagnostic, prognostic and therapeutic challenges persist. We enrolled 610 patients with different forms of CF and studied them from a clinical, biochemical, microbiological and genetic point of view. Overall, there were 125 different mutated alleles (11 with novel mutations and 10 with complex mutations) and 225 genotypes. A strong correlation between mutational patterns at the genotypic level and phenotypic macrocategories emerged. This specificity appears to largely depend on rare and individual mutations, as well as on the varying prevalence of common alleles in different clinical macrocategories. However, 19 genotypes appeared to underlie different clinical forms of the disease. The dissection of the pathway from the CFTR mutated genotype to the clinical phenotype allowed to identify at least two components of the variability usually found in the genotype–phenotype relationship. One component seems to depend on the genetic variation of CFTR, the other component on the cumulative effect of variations in other genes and cellular pathways independent from CFTR. The experimental dissection of the overall biological CFTR pathway appears to be a powerful approach for a better comprehension of the genotype–phenotype relationship. However, a change from an allele-oriented to a genotypic-oriented view of CFTR genetics is mandatory, as well as a better assessment of sources of variability within the CFTR pathway. PMID:25910067

Identifying prognostic signature in ovarian cancer using DirGenerank

PubMed Central

Wang, Jian-Yong; Chen, Ling-Ling; Zhou, Xiong-Hui

2017-01-01

Identifying the prognostic genes in cancer is essential not only for the treatment of cancer patients, but also for drug discovery. However, it's still a big challenge to select the prognostic genes that can distinguish the risk of cancer patients across various data sets because of tumor heterogeneity. In this situation, the selected genes whose expression levels are statistically related to prognostic risks may be passengers. In this paper, based on gene expression data and prognostic data of ovarian cancer patients, we used conditional mutual information to construct gene dependency network in which the nodes (genes) with more out-degrees have more chances to be the modulators of cancer prognosis. After that, we proposed DirGenerank (Generank in direct netowrk) algorithm, which concerns both the gene dependency network and genes’ correlations to prognostic risks, to identify the gene signature that can predict the prognostic risks of ovarian cancer patients. Using ovarian cancer data set from TCGA (The Cancer Genome Atlas) as training data set, 40 genes with the highest importance were selected as prognostic signature. Survival analysis of these patients divided by the prognostic signature in testing data set and four independent data sets showed the signature can distinguish the prognostic risks of cancer patients significantly. Enrichment analysis of the signature with curated cancer genes and the drugs selected by CMAP showed the genes in the signature may be drug targets for therapy. In summary, we have proposed a useful pipeline to identify prognostic genes of cancer patients. PMID:28615526

Prognostic significance of peripheral monocyte count in patients with extranodal natural killer/T-cell lymphoma.

PubMed

Huang, Jia-Jia; Li, Ya-Jun; Xia, Yi; Wang, Yu; Wei, Wen-Xiao; Zhu, Ying-Jie; Lin, Tong-Yu; Huang, Hui-Qiang; Jiang, Wen-Qi; Li, Zhi-Ming

2013-05-03

Extranodal natural killer/T-cell lymphoma (ENKL) has heterogeneous clinical manifestations and prognosis. This study aims to evaluate the prognostic impact of absolute monocyte count (AMC) in ENKL, and provide some immunologically relevant information for better risk stratification in patients with ENKL. Retrospective data from 163 patients newly diagnosed with ENKL were analyzed. The absolute monocyte count (AMC) at diagnosis was analyzed as continuous and dichotomized variables. Independent prognostic factors of survival were determined by Cox regression analysis. The AMC at diagnosis were related to overall survival (OS) and progression-free survival (PFS) in patients with ENKL. Multivariate analysis identified AMC as independent prognostic factors of survival, independent of International Prognostic Index (IPI) and Korean prognostic index (KPI). The prognostic index incorporating AMC and absolute lymphocyte count (ALC), another surrogate factor of immune status, could be used to stratify all 163 patients with ENKL into different prognostic groups. For patients who received chemotherapy followed by radiotherapy (102 cases), the three AMC/ALC index categories identified patients with significantly different survivals. When superimposed on IPI or KPI categories, the AMC/ALC index was better able to identify high-risk patients in the low-risk IPI or KPI category. The baseline peripheral monocyte count is shown to be an effective prognostic indicator of survival in ENKL patients. The prognostic index related to tumor microenvironment might be helpful to identify high-risk patients with ENKL.

Validation and Refinement of Chronic Lung Allograft Dysfunction Phenotypes in Bilateral and Single Lung Recipients

PubMed Central

Todd, Jamie L.; Zhang, Alice; Li, Ning; Mayalall, Aradhna; Finlen Copeland, C. Ashley; Shino, Michael; Pavlisko, Elizabeth N.; Wallace, W. Dean; Gregson, Aric; Ross, David J.; Saggar, Rajan; Lynch, Joseph P.; Belperio, John; Snyder, Laurie D.; Palmer, Scott M.

2016-01-01

Rationale: The clinical course of chronic lung allograft dysfunction (CLAD) is heterogeneous. Forced vital capacity (FVC) loss at onset, which may suggest a restrictive phenotype, was associated with worse survival for bilateral lung transplant recipients in one previously published single-center study. Objectives: We sought to replicate the significance of FVC loss in an independent, retrospectively identified cohort of bilateral lung transplant recipients and to investigate extended application of this approach to single lung recipients. Methods: FVC loss and other potential predictors of survival after the onset of CLAD were assessed using Kaplan-Meier and Cox proportional hazards models. Measurements and Main Results: FVC loss at the onset of CLAD was associated with higher mortality in an independent cohort of bilateral lung transplant recipients (hazard ratio [HR], 2.75; 95% confidence interval [CI], 2.02–3.73; P < 0.0001) and in a multicenter cohort of single lung recipients (HR, 1.80; 95% CI, 1.09–2.98; P = 0.02). Including all subjects, the deleterious impact of FVC loss on survival persisted after adjustment for other relevant clinical variables (HR, 2.36; 95% CI, 1.77–3.15; P < 0.0001). In patients who develop CLAD without FVC loss, chest computed tomography features suggestive of pleural or parenchymal fibrosis also predicted worse survival in both bilateral (HR, 2.01; 95% CI, 1.16–5.20; P = 0.02) and single recipients (HR, 2.47; 95% CI, 1.24–10.57; P = 0.02). Conclusions: We independently validated the prognostic significance of FVC loss for bilateral lung recipients and demonstrated that this approach to CLAD classification also confers prognostic information for single lung transplant recipients. Improved understanding of these discrete phenotypes is critical to the development of effective therapies. PMID:27144793

Third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15.

PubMed

Olander, E; Stamberg, J; Steinberg, L; Wulfsberg, E A

2000-07-31

We report on a boy with mosaicism for trisomy 15 and Prader-Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype-genotype differences are useful to guide the work-up of patients with suspected PWS and to provide prognostic counseling for families.

Mitochondrial “power” drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer

PubMed Central

Fiorillo, Marco; Sotgia, Federica; Sisci, Diego; Cappello, Anna Rita; Lisanti, Michael P.

2017-01-01

Here, we identified two new molecular targets, which are functionally sufficient to metabolically confer the tamoxifen-resistance phenotype in human breast cancer cells. Briefly, ~20 proteins were first selected as potential candidates, based on unbiased proteomics analysis, using tamoxifen-resistant cell lines. Then, the cDNAs of the most promising candidates were systematically transduced into MCF-7 cells. Remarkably, NQO1 and GCLC were both functionally sufficient to autonomously confer a tamoxifen-resistant metabolic phenotype, characterized by i) increased mitochondrial biogenesis, ii) increased ATP production and iii) reduced glutathione levels. Thus, we speculate that pharmacological inhibition of NQO1 and GCLC may be new therapeutic strategies for overcoming tamoxifen-resistance in breast cancer patients. In direct support of this notion, we demonstrate that treatment with a known NQO1 inhibitor (dicoumarol) is indeed sufficient to revert the tamoxifen-resistance phenotype. As such, these findings could have important translational significance for the prevention of tumor recurrence in ER(+) breast cancers, which is due to an endocrine resistance phenotype. Importantly, we also show here that NQO1 has significant prognostic value as a biomarker for the prediction of tumor recurrence. More specifically, higher levels of NQO1 mRNA strongly predict patient relapse in high-risk ER(+) breast cancer patients receiving endocrine therapy (mostly tamoxifen; H.R. > 2.15; p = 0.007). PMID:28411284

Epithelial–mesenchymal transition-associated secretory phenotype predicts survival in lung cancer patients

PubMed Central

Reka, Ajaya Kumar; Chen, Guoan; Keshamouni, Venkateshwar G.

2014-01-01

In cancer cells, the process of epithelial–mesenchymal transition (EMT) confers migratory and invasive capacity, resistance to apoptosis, drug resistance, evasion of host immune surveillance and tumor stem cell traits. Cells undergoing EMT may represent tumor cells with metastatic potential. Characterizing the EMT secretome may identify biomarkers to monitor EMT in tumor progression and provide a prognostic signature to predict patient survival. Utilizing a transforming growth factor-β-induced cell culture model of EMT, we quantitatively profiled differentially secreted proteins, by GeLC-tandem mass spectrometry. Integrating with the corresponding transcriptome, we derived an EMT-associated secretory phenotype (EASP) comprising of proteins that were differentially upregulated both at protein and mRNA levels. Four independent primary tumor-derived gene expression data sets of lung cancers were used for survival analysis by the random survival forests (RSF) method. Analysis of 97-gene EASP expression in human lung adenocarcinoma tumors revealed strong positive correlations with lymph node metastasis, advanced tumor stage and histological grade. RSF analysis built on a training set (n = 442), including age, sex and stage as variables, stratified three independent lung cancer data sets into low-, medium- and high-risk groups with significant differences in overall survival. We further refined EASP to a 20 gene signature (rEASP) based on variable importance scores from RSF analysis. Similar to EASP, rEASP predicted survival of both adenocarcinoma and squamous carcinoma patients. More importantly, it predicted survival in the early-stage cancers. These results demonstrate that integrative analysis of the critical biological process of EMT provides mechanism-based and clinically relevant biomarkers with significant prognostic value. PMID:24510113

Prognostic categories and timing of negative prognostic communication from critical care physicians to family members at end-of-life in an intensive care unit.

PubMed

Gutierrez, Karen M

2013-09-01

Negative prognostic communication is often delayed in intensive care units, which limits time for families to prepare for end-of-life. This descriptive study, informed by ethnographic methods, was focused on exploring critical care physician communication of negative prognoses to families and identifying timing influences. Prognostic communication of critical care physicians to nurses and family members was observed and physicians and family members were interviewed. Physician perception of prognostic certainty, based on an accumulation of empirical data, and the perceived need for decision-making, drove the timing of prognostic communication, rather than family needs. Although prognoses were initially identified using intuitive knowledge for patients in one of the six identified prognostic categories, utilizing decision-making to drive prognostic communication resulted in delayed prognostic communication to families until end-of-life (EOL) decisions could be justified with empirical data. Providers will better meet the needs of families who desire earlier prognostic information by separating prognostic communication from decision-making and communicating the possibility of a poor prognosis based on intuitive knowledge, while acknowledging the uncertainty inherent in prognostication. This sets the stage for later prognostic discussions focused on EOL decisions, including limiting or withdrawing treatment, which can be timed when empirical data substantiate intuitive prognoses. This allows additional time for families to anticipate and prepare for end-of-life decision-making. © 2012 John Wiley & Sons Ltd.

Glycolytic activity in breast cancer using 18F-FDG PET/CT as prognostic predictor: A molecular phenotype approach.

PubMed

Garcia Vicente, A M; Soriano Castrejón, A; Amo-Salas, M; Lopez Fidalgo, J F; Muñoz Sanchez, M M; Alvarez Cabellos, R; Espinosa Aunion, R; Muñoz Madero, V

2016-01-01

To explore the relationship between basal (18)F-FDG uptake in breast tumors and survival in patients with breast cancer (BC) using a molecular phenotype approach. This prospective and multicentre study included 193 women diagnosed with BC. All patients underwent an (18)F-FDG PET/CT prior to treatment. Maximum standardized uptake value (SUVmax) in tumor (T), lymph nodes (N), and the N/T index was obtained in all the cases. Metabolic stage was established. As regards biological prognostic parameters, tumors were classified into molecular sub-types and risk categories. Overall survival (OS) and disease free survival (DFS) were obtained. An analysis was performed on the relationship between semi-quantitative metabolic parameters with molecular phenotypes and risk categories. The effect of molecular sub-type and risk categories in prognosis was analyzed using Kaplan-Meier and univariate and multivariate tests. Statistical differences were found in both SUVT and SUVN, according to the molecular sub-types and risk classifications, with higher semi-quantitative values in more biologically aggressive tumors. No statistical differences were observed with respect to the N/T index. Kaplan-Meier analysis revealed that risk categories were significantly related to DFS and OS. In the multivariate analysis, metabolic stage and risk phenotype showed a significant association with DFS. High-risk phenotype category showed a worst prognosis with respect to the other categories with higher SUVmax in primary tumor and lymph nodes. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

Deliverability and efficacy of R-CHOP chemotherapy in very elderly patients with diffuse large B-cell lymphoma: an Australian retrospective analysis.

PubMed

Millar, A; Ellis, M; Mollee, P; Cochrane, T; Fletcher, J; Caudron, A; Webster, B; Trotman, J

2015-11-01

Elderly patients with diffuse large B-cell lymphoma (DLBCL) have an inferior prognosis, due in part to advanced age and pre-existing comorbidities, with reduced tolerability and deliverability of standard R-CHOP chemotherapy. To examine the deliverability, toxicity and efficacy of R-CHOP and the prevalence of the germinal and non-germinal phenotype DLBCL in an elderly Australian cohort. This retrospective analysis included patients ≥75 years diagnosed with DLBCL. Comprehensive chemotherapy and toxicity data were collected for patients treated with R-CHOP. Baseline demographics and chemotherapy characteristics were compared with progression-free (PFS) and overall survival (OS). Immunohistochemical staining identified the prevalence of the non-germinal centre (non-GCB) phenotype. Of the 111 patients, 92 (83%) commenced R-CHOP with 26/92 (28%) receiving ≤4 cycles. Median average relative dose (ARD) was 0.80 (0.07-1.17). Median average relative dose intensity (ARDI) was 0.89 (0.33-1.18). Serious adverse events occurred in 77% of patients with ≥Gd3 adverse events in 74%. Overall response rate was 85%. Two-year PFS was 63% and OS 74%. ARD and performance status ≥2 were significant prognostic factors for PFS and OS but not ARDI. Non-GCB-phenotype was identified in 44/72 (61%) of patients with immunohistochemical data. Despite high response rates and respectable survival estimates, the absence of standard therapy in 17% of patients, and dose reductions and serious toxicity of R-CHOP in this Australian cohort highlights the need for the development of less toxic yet efficacious treatments for very elderly patients with DLBCL. The high prevalence of the non-GCB phenotype highlights the potential value of targeted biological therapy for this demographic. © 2015 Royal Australasian College of Physicians.

Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel.

PubMed

Aharoni, Sharon; Barwick, Katy E S; Straussberg, Rachel; Harlalka, Gaurav V; Nevo, Yoram; Chioza, Barry A; McEntagart, Meriel M; Mimouni-Bloch, Aviva; Weedon, Michael; Crosby, Andrew H

2016-11-16

CMT-2 is a clinically and genetically heterogeneous group of peripheral axonal neuropathies characterized by slowly progressive weakness and atrophy of distal limb muscles resulting from length-dependent motor and sensory neurodegeneration. Classical giant axonal neuropathy (GAN) is an autosomal recessively inherited progressive neurodegenerative disorder of the peripheral and central nervous systems, typically diagnosed in early childhood and resulting in death by the end of the third decade. Distinctive phenotypic features are the presence of "kinky" hair and long eyelashes. The genetic basis of the disease has been well established, with over 40 associated mutations identified in the gene GAN, encoding the BTB-KELCH protein gigaxonin, involved in intermediate filament regulation. An Illumina Human CytoSNP-12 array followed by whole exome sequence analysis was used to identify the disease associated gene mutation in a large consanguineous family diagnosed with Charcot-Marie-Tooth disease type 2 (CMT-2) from which all but one affected member had straight hair. Here we report the identification of a novel GAN missense mutation underlying the CMT-2 phenotype observed in this family. Although milder forms of GAN, with and without the presence of kinky hair have been reported previously, a phenotype distinct from that was investigated in this study. All family members lacked common features of GAN, including ataxia, nystagmus, intellectual disability, seizures, and central nervous system involvement. Our findings broaden the spectrum of phenotypes associated with GAN mutations and emphasize a need to proceed with caution when providing families with diagnostic or prognostic information based on either clinical or genetic findings alone.

The application of artificial intelligence to microarray data: identification of a novel gene signature to identify bladder cancer progression.

PubMed

Catto, James W F; Abbod, Maysam F; Wild, Peter J; Linkens, Derek A; Pilarsky, Christian; Rehman, Ishtiaq; Rosario, Derek J; Denzinger, Stefan; Burger, Maximilian; Stoehr, Robert; Knuechel, Ruth; Hartmann, Arndt; Hamdy, Freddie C

2010-03-01

New methods for identifying bladder cancer (BCa) progression are required. Gene expression microarrays can reveal insights into disease biology and identify novel biomarkers. However, these experiments produce large datasets that are difficult to interpret. To develop a novel method of microarray analysis combining two forms of artificial intelligence (AI): neurofuzzy modelling (NFM) and artificial neural networks (ANN) and validate it in a BCa cohort. We used AI and statistical analyses to identify progression-related genes in a microarray dataset (n=66 tumours, n=2800 genes). The AI-selected genes were then investigated in a second cohort (n=262 tumours) using immunohistochemistry. We compared the accuracy of AI and statistical approaches to identify tumour progression. AI identified 11 progression-associated genes (odds ratio [OR]: 0.70; 95% confidence interval [CI], 0.56-0.87; p=0.0004), and these were more discriminate than genes chosen using statistical analyses (OR: 1.24; 95% CI, 0.96-1.60; p=0.09). The expression of six AI-selected genes (LIG3, FAS, KRT18, ICAM1, DSG2, and BRCA2) was determined using commercial antibodies and successfully identified tumour progression (concordance index: 0.66; log-rank test: p=0.01). AI-selected genes were more discriminate than pathologic criteria at determining progression (Cox multivariate analysis: p=0.01). Limitations include the use of statistical correlation to identify 200 genes for AI analysis and that we did not compare regression identified genes with immunohistochemistry. AI and statistical analyses use different techniques of inference to determine gene-phenotype associations and identify distinct prognostic gene signatures that are equally valid. We have identified a prognostic gene signature whose members reflect a variety of carcinogenic pathways that could identify progression in non-muscle-invasive BCa. 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Prognostic significance of peripheral monocyte count in patients with extranodal natural killer/T-cell lymphoma

PubMed Central

2013-01-01

Background Extranodal natural killer/T-cell lymphoma (ENKL) has heterogeneous clinical manifestations and prognosis. This study aims to evaluate the prognostic impact of absolute monocyte count (AMC) in ENKL, and provide some immunologically relevant information for better risk stratification in patients with ENKL. Methods Retrospective data from 163 patients newly diagnosed with ENKL were analyzed. The absolute monocyte count (AMC) at diagnosis was analyzed as continuous and dichotomized variables. Independent prognostic factors of survival were determined by Cox regression analysis. Results The AMC at diagnosis were related to overall survival (OS) and progression-free survival (PFS) in patients with ENKL. Multivariate analysis identified AMC as independent prognostic factors of survival, independent of International Prognostic Index (IPI) and Korean prognostic index (KPI). The prognostic index incorporating AMC and absolute lymphocyte count (ALC), another surrogate factor of immune status, could be used to stratify all 163 patients with ENKL into different prognostic groups. For patients who received chemotherapy followed by radiotherapy (102 cases), the three AMC/ALC index categories identified patients with significantly different survivals. When superimposed on IPI or KPI categories, the AMC/ALC index was better able to identify high-risk patients in the low-risk IPI or KPI category. Conclusion The baseline peripheral monocyte count is shown to be an effective prognostic indicator of survival in ENKL patients. The prognostic index related to tumor microenvironment might be helpful to identify high-risk patients with ENKL. PMID:23638998

Whole-Exome Sequencing in Two Extreme Phenotypes of Response to VEGF-Targeted Therapies in Patients With Metastatic Clear Cell Renal Cell Carcinoma.

PubMed

Fay, Andre P; de Velasco, Guillermo; Ho, Thai H; Van Allen, Eliezer M; Murray, Bradley; Albiges, Laurence; Signoretti, Sabina; Hakimi, A Ari; Stanton, Melissa L; Bellmunt, Joaquim; McDermott, David F; Atkins, Michael B; Garraway, Levi A; Kwiatkowski, David J; Choueiri, Toni K

2016-07-01

Advances in next-generation sequencing have provided a unique opportunity to understand the biology of disease and mechanisms of sensitivity or resistance to specific agents. Renal cell carcinoma (RCC) is a heterogeneous disease and highly variable clinical responses have been observed with vascular endothelial growth factor (VEGF)-targeted therapy (VEGF-TT). We hypothesized that whole-exome sequencing analysis might identify genotypes associated with extreme response or resistance to VEGF-TT in metastatic (mRCC). Patients with mRCC who had received first-line sunitinib or pazopanib and were in 2 extreme phenotypes of response were identified. Extreme responders (ERs) were defined as those with partial response or complete response for 3 or more years (n=13) and primary refractory patients (PRPs) were defined as those with progressive disease within the first 3 months of therapy (n=14). International Metastatic RCC Database Consortium prognostic scores were not significantly different between the groups (P=.67). Considering the genes known to be mutated in RCC at significant frequency, PBRM1 mutations were identified in 7 ERs (54%) versus 1 PRP (7%) (P=.01). In addition, mutations in TP53 (n=4) were found only in PRPs (P=.09). Our data suggest that mutations in some genes in RCC may impact response to VEGF-TT. Copyright © 2016 by the National Comprehensive Cancer Network.

Granulin, a novel STAT3-interacting protein, enhances STAT3 transcriptional function and correlates with poorer prognosis in breast cancer

PubMed Central

Yeh, Jennifer E.; Kreimer, Simion; Walker, Sarah R.; Emori, Megan M.; Krystal, Hannah; Richardson, Andrea; Ivanov, Alexander R.; Frank, David A.

2015-01-01

Since the neoplastic phenotype of a cell is largely driven by aberrant gene expression patterns, increasing attention has been focused on transcription factors that regulate critical mediators of tumorigenesis such as signal transducer and activator of transcription 3 (STAT3). As proteins that interact with STAT3 may be key in addressing how STAT3 contributes to cancer pathogenesis, we took a proteomics approach to identify novel STAT3-interacting proteins. We performed mass spectrometry-based profiling of STAT3-containing complexes from breast cancer cells that have constitutively active STAT3 and are dependent on STAT3 function for survival. We identified granulin (GRN) as a novel STAT3-interacting protein that was necessary for both constitutive and maximal leukemia inhibitory factor (LIF)induced STAT3 transcriptional activity. GRN enhanced STAT3 DNA binding and also increased the time-integrated amount of LIF-induced STAT3 activation in breast cancer cells. Furthermore, silencing GRN neutralized STAT3-mediated tumorigenic phenotypes including viability, clonogenesis, and migratory capacity. In primary breast cancer samples, GRN mRNA levels were positively correlated with STAT3 gene expression signatures and with reduced patient survival. These studies identify GRN as a functionally important STAT3-interacting protein that may serve as an important prognostic biomarker and potential therapeutic target in breast cancer. PMID:26000098

Small biparietal diameter and head circumference are part of the phenotype instead of independent prognostic markers in fetuses with spinal dysraphism.

PubMed

Cuppen, Inge; de Bruijn, Dagmar; Geerdink, Niels; Rotteveel, Jan J; Willemsen, Michèl A A P; van Vugt, John M G; Pasman, Jaco W; Roeleveld, Nel

2015-01-01

The aim of this retrospective study was to assess the fetal biparietal diameter (BPD) and head circumference (HC) in the second trimester of pregnancy in fetuses with open spinal dysraphism. BPD and HC were measured at 16-26 weeks in 74 fetuses with open spinal dysraphism and compared with reference values. BPD was smaller in fetuses with open spinal dysraphism. Of all cases with open spinal dysraphism, 62.2% had a BPD <3rd percentile and 79.7% had a BPD <10th percentile. Of all patients, 54.1% had an HC <3rd percentile and 74.3% had an HC <10th percentile. Almost all fetuses with open neural tube defects have a smaller BPD and HC at 16-26 weeks compared with reference values, which implicates that this is part of the phenotype of children with open spinal dysraphism instead of an independent prognostic marker for a poor cognitive outcome. © 2014 S. Karger AG, Basel.

Correlation of karyotype and immunophenotype in childhood acute lymphoblastic leukemia; experience at the National Cancer Institute, Cairo University, Egypt.

PubMed

Hamouda, Faiza; El-Sissy, Azza H; Radwan, Ashraf K; Hussein, Hany; Gadallah, Farida H; Al-Sharkawy, Nahla; Sedhom, Eman; Ebeid, Emad; Salem, Shereen I

2007-06-01

To identify chromosomal pattern among the major immunophenotypic subgroups in Egyptian children with ALL, and its correlation with clinical presentation and disease free survival. Cytogenetic and immunophenotypic analysis were done for all patients. Patients received ALL-PNCI-III/98 chemotherapy protocol used at NCI, Cairo University. The frequency of pseudodiploidy and normal karyotype in the whole group was 42.9% and 33.3% respectively. The frequency of pseudodiploidy was 36.8% in CALLA positive early pre B, 30.7% in pre B cases, 71.4% in T cell cases and 100% in mature B cell cases. At 12 months, DFS was 50% for pseudodiploid group having pre B phenotype, compared to 16.6% for pseudodiploid group with CALLA positive early pre B ALL. Sixteen percent of the studied cases showed T cell phenotype, 71.4% of them showed pseudodiploid karyotype, all of them had high risk features. Hyperdiploidy was found in 31.5% of CALLA positive early pre B cases and was associated with favorable prognostic features and DFS of 66.6% at 12 months. Hyperdiploidy of >50 chromosome represented 62.5% of hyperdipoid cases, 80% of them were CALLA positive early pre B ALL carrying good risk features. Fifty percent of normal karyotypic patients showed pre B phenotype, while 42.8% showed CALLA positive early pre B ALL. Their age, TLC, DFS, were almost comparable. CALLA early pre B phenotype has a positive impact on chromosomal pattern having best outcome among patients with hyperdiploidy. The Pseudodiploid karyotype carries a better outcome with pre B phenotype.

miR-181d/MALT1 regulatory axis attenuates mesenchymal phenotype through NF-κB pathways in glioblastoma.

PubMed

Yang, Fan; Liu, Xing; Liu, Yanwei; Liu, Yuqing; Zhang, Chuanbao; Wang, Zheng; Jiang, Tao; Wang, Yongzhi

2017-06-28

The mesenchymal (MES) subtype of glioblastoma (GBM) indicated a more malignant phenotype and worse prognosis compared with their proneural (PN) counterpart. The plasticity between PN and MES transcriptome signatures provided an approach for clinical intervention. However, few miRNAs have been identified to participate in the shift between subtypes. Here, we utilized transcriptomic data and experimental evidences to prove that miR-181d was a novel regulator of NFκB signaling pathway by directly repressing MALT1, leading to induced PN markers and reduced MES genes. Functionally, ectopic expression of miR-181d suppressed GBM cell proliferation, colony formation and anchor-independent growth, as well as migration, invasion and tube formation. Moreover, miR-181d overexpression increased radio- and chemo-sensitivity for GBM cells. Rescue of MALT1 could partially reverse the effects of miR-181d in GBM malignant behaviors. Clinically, miR-181d could serve as a prognostic indicator for GBM patients. Taken together, we concluded that loss of miR-181d contributes to aggressive biological processes associated with MES phenotype via NFκB signaling, which broaden our insights into the underlying mechanisms in subtype transition and miRNA-based tailored medicine for GBM management. Copyright © 2017 Elsevier B.V. All rights reserved.

Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival

PubMed Central

Fink, Stephen P.; Myeroff, Lois L.; Kariv, Revital; Platzer, Petra; Xin, Baozhong; Mikkola, Debra; Lawrence, Earl; Morris, Nathan; Nosrati, Arman; Willson, James K. V.; Willis, Joseph; Veigl, Martina; Barnholtz-Sloan, Jill S.; Wang, Zhenghe; Markowitz, Sanford D.

2015-01-01

Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. We originally identified KIAA1199 (now officially called CEMIP) as a transcript highly induced in colon cancer: initially designating the transcript as Colon Cancer Secreted Protein 1. We molecularly characterized CEMIP expression both at the mRNA and protein level and found it is a secreted protein induced an average of 54-fold in colon cancer. Knockout of CEMIPreduced the ability of human colon cancer cells to form xenograft tumors in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. We find CEMIP mRNA overexpression correlates with poorer patient survival. In stage III only (n = 31) or in combined stage II plus stage III colon cancer cases (n = 73), 5-year overall survival was significantly better (p = 0.004 and p = 0.0003, respectively) among patients with low CEMIP expressing tumors than those with high CEMIP expressing tumors. These results demonstrate that CEMIP directly facilitates colon tumor growth, and high CEMIP expression correlates with poor outcome in stage III and in stages II+III combined cohorts. We present CEMIP as a candidate prognostic marker for colon cancer and a potential therapeutic target. PMID:26437221

Checkpoint Kinase 1 Expression Predicts Poor Prognosis in Nigerian Breast Cancer Patients.

PubMed

Ebili, Henry Okuchukwu; Iyawe, Victoria O; Adeleke, Kikelomo Rachel; Salami, Babatunde Abayomi; Banjo, Adekunbiola Aina; Nolan, Chris; Rakha, Emad; Ellis, Ian; Green, Andrew; Agboola, Ayodeji Olayinka Johnson

2018-02-01

Checkpoint kinase 1 (CHEK1), a DNA damage sensor and cell death pathway stimulator, is regarded as an oncogene in tumours, where its activities are considered essential for tumourigenesis and the survival of cancer cells treated with chemotherapy and radiotherapy. In breast cancer, CHEK1 expression has been associated with an aggressive tumour phenotype, the triple-negative breast cancer subtype, an aberrant response to tamoxifen, and poor prognosis. However, the relevance of CHEK1 expression has, hitherto, not been investigated in an indigenous African population. We therefore aimed to investigate the clinicopathological, biological, and prognostic significance of CHEK1 expression in a cohort of Nigerian breast cancer cases. Tissue microarrays of 207 Nigerian breast cancer cases were tested for CHEK1 expression using immunohistochemistry. The clinicopathological, molecular, and prognostic characteristics of CHEK1-positive tumours were determined using the Chi-squared test and Kaplan-Meier and Cox regression analyses in SPSS Version 16. Nuclear expression of CHEK1 was present in 61% of breast tumours and was associated with tumour size, triple-negative cancer, basal-like phenotype, the epithelial-mesenchymal transition, p53 over-expression, DNA homologous repair pathway dysfunction, and poor prognosis. The rate expression of CHEK1 is high in Nigerian breast cancer cases and is associated with an aggressive phenotype and poor prognosis.

Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

PubMed Central

Peinado, Héctor; Alečković, Maša; Lavotshkin, Simon; Matei, Irina; Costa-Silva, Bruno; Moreno-Bueno, Gema; Hergueta-Redondo, Marta; Williams, Caitlin; García-Santos, Guillermo; Nitadori-Hoshino, Ayuko; Hoffman, Caitlin; Badal, Karen; Garcia, Benjamin A.; Callahan, Margaret K.; Yuan, Jianda; Martins, Vilma R.; Skog, Johan; Kaplan, Rosandra N.; Brady, Mary S.; Wolchok, Jedd D.; Chapman, Paul B.; Kang, Yibin; Bromberg, Jacqueline; Lyden, David

2013-01-01

Tumor-derived exosomes are emerging mediators of tumorigenesis with tissue-specific addresses and messages. We explored the function of melanoma-derived exosomes in the formation of primary tumor and metastases in mouse and human subjects. Exosomes from highly metastatic melanoma increased the metastatic behavior of primary tumors by permanently “educating” bone marrow (BM) progenitors via the MET receptor. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitors towards a c-Kit+Tie2+Met+ pro-vasculogenic phenotype. Reducing Met expression in exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was elevated in circulating CD45−C-KITlow/+TIE2+ BM progenitors from metastatic melanoma subjects. RAB1a, RAB5b, RAB7, and RAB27a were highly expressed in melanoma cells and Rab27a RNA interference decreased exosome production, preventing BM education, tumor growth and metastasis. Finally, we identified an exosome-specific “melanoma signature” with prognostic and therapeutic potential, comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. PMID:22635005

Prognostic value of miliary versus non-miliary sub-staging in advanced ovarian cancer.

PubMed

Eng, Kevin H; Morrell, Kayla; Starbuck, Kristen; Spring-Robinson, Chandra; Khan, Aalia; Cleason, Dana; Akman, Levent; Zsiros, Emese; Odunsi, Kunle; Szender, J Brian

2017-07-01

The presence of miliary disease during initial ovarian cancer debulking may reflect a distinct mode of peritoneal spread independent from size-based tumor staging and may explain variation in response to treatment and survival outcomes. To infer the prevalence, presentation and clinical implications of miliary disease we reviewed existing surgical records. Reports were available for 1008 primary debulking surgeries for ovarian, primary peritoneal or fallopian tube cancer between 2001 and 2015 (685 reports from 2005 to 2015). Clinical outcome data was available for 938 patients. We analyzed a high-stage sub-cohort for survival (N=436). Most records were evaluable for miliary disease (761/938); for these, the miliary phenotype was highly prevalent (249/761, 32.7%) and often accompanied by ascites (185/249, 74%). While optimal debulking rates were unaffected by miliary disease, total resection (R0) rates were poorer. Liver, stomach, spleen or bladder appeared to be sporadically involved while the omentum, mesentery, bowel, peritoneum and diaphragm were affected simultaneously (Spearman rho>0.5). Overall, miliary disease was associated with worse progression free survival, overall survival, and time from relapse to death independent of stage. Survival effects were particularly strong for Stage IV disease where median overall survival varied by over 30months (log-rank p=0.002). Miliary disease is an identifiable surgical phenotype reflecting a distinct clinical trajectory that adds prognostic information to standard disease burden-based staging. These findings should permit further retrospective investigation in a wider cohort and prompt the consideration of prospective structured operative reporting standards and treatment strategies. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Notch Signaling Activation Is Associated with Patient Mortality and Increased FGF1-Mediated Invasion in Squamous Cell Carcinoma of the Oral Cavity.

PubMed

Weaver, Alice N; Burch, M Benjamin; Cooper, Tiffiny S; Della Manna, Deborah L; Wei, Shi; Ojesina, Akinyemi I; Rosenthal, Eben L; Yang, Eddy S

2016-09-01

Oral squamous cell carcinoma (OSCC) is a cancer subtype that lacks validated prognostic and therapeutic biomarkers, and human papillomavirus status has not proven beneficial in predicting patient outcomes. A gene expression pathway analysis was conducted using OSCC patient specimens to identify molecular targets that may improve management of this disease. RNA was isolated from 19 OSCCs treated surgically at the University of Alabama at Birmingham (UAB; Birmingham, AL) and evaluated using the NanoString nCounter system. Results were confirmed using the oral cavity subdivision of the Head and Neck Squamous Cell Carcinoma Cancer (HNSCC) study generated by The Cancer Genome Atlas (TCGA) Research Network. Further characterization of the in vitro phenotype produced by Notch pathway activation in HNSCC cell lines included gene expression, proliferation, cell cycle, migration, invasion, and radiosensitivity. In both UAB and TCGA samples, Notch pathway upregulation was significantly correlated with patient mortality status and with expression of the proinvasive gene FGF1 In vitro Notch activation in HNSCC cells increased transcription of FGF1 and induced a marked increase in cell migration and invasion, which was fully abrogated by FGF1 knockdown. These results reveal that increased Notch pathway signaling plays a role in cancer progression and patient outcomes in OSCC. Accordingly, the Notch-FGF interaction should be further studied as a prognostic biomarker and potential therapeutic target for OSCC. Patients with squamous cell carcinoma of the oral cavity who succumb to their disease are more likely to have upregulated Notch signaling, which may mediate a more invasive phenotype through increased FGF1 transcription. Mol Cancer Res; 14(9); 883-91. ©2016 AACR. ©2016 American Association for Cancer Research.

Clinical potentials of methylator phenotype in stage 4 high-risk neuroblastoma: an open challenge.

PubMed

Banelli, Barbara; Merlo, Domenico Franco; Allemanni, Giorgio; Forlani, Alessandra; Romani, Massimo

2013-01-01

Approximately 20% of stage 4 high-risk neuroblastoma patients are alive and disease-free 5 years after disease onset while the remaining experience rapid and fatal progression. Numerous findings underline the prognostic role of methylation of defined target genes in neuroblastoma without taking into account the clinical and biological heterogeneity of this disease. In this report we have investigated the methylation of the PCDHB cluster, the most informative member of the "Methylator Phenotype" in neuroblastoma, hypothesizing that if this epigenetic mark can predict overall and progression free survival in high-risk stage 4 neuroblastoma, it could be utilized to improve the risk stratification of the patients, alone or in conjunction with the previously identified methylation of the SFN gene (14.3.3sigma) that can accurately predict outcome in these patients. We have utilized univariate and multivariate models to compare the prognostic power of PCDHB methylation in terms of overall and progression free survival, quantitatively determined by pyrosequencing, with that of other markers utilized for the patients' stratification utilizing methylation thresholds calculated on neuroblastoma at stage 1-4 and only on stage 4, high-risk patients. Our results indicate that PCDHB accurately distinguishes between high- and intermediate/low risk stage 4 neuroblastoma in agreement with the established risk stratification criteria. However PCDHB cannot predict outcome in the subgroup of stage 4 patients at high-risk whereas methylation levels of SFN are suggestive of a "methylation gradient" associated with tumor aggressiveness as suggested by the finding of a higher threshold that defines a subset of patients with an extremely severe disease (OS <24 months). Because of the heterogeneity of neuroblastoma we believe that clinically relevant methylation markers should be selected and tested on homogeneous groups of patients rather than on patients at all stages.

Accumulation of FOXP3+T-cells in the tumor microenvironment is associated with an epithelial-mesenchymal-transition-type tumor budding phenotype and is an independent prognostic factor in surgically resected pancreatic ductal adenocarcinoma

PubMed Central

Wartenberg, Martin; Zlobec, Inti; Perren, Aurel; Koelzer, Viktor Hendrik; Gloor, Beat; Lugli, Alessandro; Eva, Karamitopoulou

2015-01-01

Here we explore the role of the interplay between host immune response and epithelial-mesenchymal-transition (EMT)-Type tumor-budding on the outcome of pancreatic adenocarcinoma (PDAC). CD4+, CD8+, and FOXP3+T-cells as well as iNOS+ (M1) and CD163+-macrophages (M2) were assessed on multipunch tissue-microarrays containing 120 well-characterized PDACs, precursor lesions (PanINs) and corresponding normal tissue. Counts were normalized for the percentage of tumor/spot and associated with the clinico-pathological features, including peritumoral (PTB) and intratumoral (ITB) EMT-Type tumor-budding and outcome. Increased FOXP3+T-cell-counts and CD163-macrophages and decreased CD8+T-cell-counts were observed in PDACs compared with normal tissues and PanINs (p < 0.0001). Increased peritumoral FOXP3+T-cell-counts correlated significantly with venous invasion, distant metastasis, R1-status, high-grade ITB, PTB and independently with reduced survival. Increased intratumoral FOXP3+T-cells correlated with lymphatic invasion, N1-stage, PTB and marginally with adverse outcome. High peritumoral CD163-counts correlated with venous invasion, PTB and ITB. High intratumoral CD163-counts correlated with higher T-stage and PTB. PDAC-microenvironment displays a tumor-favoring immune-cell composition especially in the immediate environment of the tumor-buds that promotes further growth and indicates a close interaction of the immune response with the EMT-process. Increased peritumoral FOXP3+T-cell density is identified as an independent adverse prognostic factor in PDAC. Patients with phenotypically aggressive PDACs may profit from targeted immunotherapy against FOXP3. PMID:25669968

Phenotype in combination with genotype improves outcome prediction in acute myeloid leukemia: a report from Children’s Oncology Group protocol AAML0531

PubMed Central

Voigt, Andrew P.; Brodersen, Lisa Eidenschink; Alonzo, Todd A.; Gerbing, Robert B.; Menssen, Andrew J.; Wilson, Elisabeth R.; Kahwash, Samir; Raimondi, Susana C.; Hirsch, Betsy A.; Gamis, Alan S.; Meshinchi, Soheil; Wells, Denise A.; Loken, Michael R.

2017-01-01

Diagnostic biomarkers can be used to determine relapse risk in acute myeloid leukemia, and certain genetic aberrancies have prognostic relevance. A diagnostic immunophenotypic expression profile, which quantifies the amounts of distinct gene products, not just their presence or absence, was established in order to improve outcome prediction for patients with acute myeloid leukemia. The immunophenotypic expression profile, which defines each patient’s leukemia as a location in 15-dimensional space, was generated for 769 patients enrolled in the Children’s Oncology Group AAML0531 protocol. Unsupervised hierarchical clustering grouped patients with similar immunophenotypic expression profiles into eleven patient cohorts, demonstrating high associations among phenotype, genotype, morphology, and outcome. Of 95 patients with inv(16), 79% segregated in Cluster A. Of 109 patients with t(8;21), 92% segregated in Clusters A and B. Of 152 patients with 11q23 alterations, 78% segregated in Clusters D, E, F, G, or H. For both inv(16) and 11q23 abnormalities, differential phenotypic expression identified patient groups with different survival characteristics (P<0.05). Clinical outcome analysis revealed that Cluster B (predominantly t(8;21)) was associated with favorable outcome (P<0.001) and Clusters E, G, H, and K were associated with adverse outcomes (P<0.05). Multivariable regression analysis revealed that Clusters E, G, H, and K were independently associated with worse survival (P range <0.001 to 0.008). The Children’s Oncology Group AAML0531 trial: clinicaltrials.gov Identifier: 00372593. PMID:28883080

Promising personalized therapeutic options for diffuse large B-cell Lymphoma Subtypes with oncogene addictions.

PubMed

Steinhardt, James J; Gartenhaus, Ronald B

2012-09-01

Currently, two major classification systems segregate diffuse large B-cell lymphoma (DLBCL) into subtypes based on gene expression profiles and provide great insights about the oncogenic mechanisms that may be crucial for lymphomagenesis as well as prognostic information regarding response to current therapies. However, these current classification systems primarily look at expression and not dependency and are thus limited to inductive or probabilistic reasoning when evaluating alternative therapeutic options. The development of a deductive classification system that identifies subtypes in which all patients with a given phenotype require the same oncogenic drivers, and would therefore have a similar response to a rational therapy targeting the essential drivers, would significantly advance the treatment of DLBCL. This review highlights the putative drivers identified as well as the work done to identify potentially dependent populations. These studies integrated genomic analysis and functional screens to provide a rationale for targeted therapies within defined populations. Personalizing treatments by identifying patients with oncogenic dependencies via genotyping and specifically targeting the responsible drivers may constitute a novel approach for the treatment of DLBCL. ©2012 AACR.

New prognostic model for extranodal natural killer/T cell lymphoma, nasal type.

PubMed

Cai, Qingqing; Luo, Xiaolin; Zhang, Guanrong; Huang, Huiqiang; Huang, Hui; Lin, Tongyu; Jiang, Wenqi; Xia, Zhongjun; Young, Ken H

2014-09-01

Extranodal natural killer/T cell lymphoma, nasal type (ENKTL) is an aggressive disease with a poor prognosis, requiring risk stratification in affected patients. We designed a new prognostic model specifically for ENKTL to identify high-risk patients who need more aggressive therapy. We retrospectively reviewed 158 patients who were newly diagnosed with ENKTL. The estimated 5-year overall survival rate was 39.4 %. Independent prognostic factors included total protein (TP) <60 g/L, fasting blood glucose (FBG) >100 mg/dL, and Korean Prognostic Index (KPI) score ≥2. We constructed a new prognostic model by combining these prognostic factors: group 1 (64 cases (41.0 %)), no adverse factors; group 2 (58 cases (37.2 %)), one adverse factor; and group 3 (34 cases (21.8 %)), two or three adverse factors. The 5-year overall survival (OS) rates of these groups were 66.7, 23.0, and 5.9 %, respectively (p < 0.001). Our new prognostic model had a better prognostic value than did the KPI model alone (p < 0.001). Our proposed prognostic model for ENKTL, including the newly identified prognostic indicators, TP and FBG, demonstrated a balanced distribution of patients into different risk groups with better prognostic discrimination compared with the KPI model alone.

Gene Expression Profiling of Benign and Malignant Pheochromocytoma

PubMed Central

BROUWERS, FREDERIEKE M.; ELKAHLOUN, ABDEL G.; MUNSON, PETER J.; EISENHOFER, GRAEME; BARB, JENNIFER; LINEHAN, W. MARSTON; LENDERS, JACQUES W.M.; DE KRIJGER, RONALD; MANNELLI, MASSIMO; UDELSMAN, ROBERT; OCAL, IDRIS T.; SHULKIN, BARRY L.; BORNSTEIN, STEFAN R.; BREZA, JAN; KSINANTOVA, LUCIA; PACAK, KAREL

2016-01-01

There are currently no reliable diagnostic and prognostic markers or effective treatments for malignant pheochromocytoma. This study used oligonucleotide microarrays to examine gene expression profiles in pheochromocytomas from 90 patients, including 20 with malignant tumors, the latter including metastases and primary tumors from which metastases developed. Other subgroups of tumors included those defined by tissue norepinephrine compared to epinephrine contents (i.e., noradrenergic versus adrenergic phenotypes), adrenal versus extra-adrenal locations, and presence of germline mutations of genes pre-disposing to the tumor. Correcting for the confounding influence of nora-drenergic versus adrenergic catecholamine phenotype by the analysis of variance revealed a larger and more accurate number of genes that discriminated benign from malignant pheochromocytomas than when the confounding influence of catecholamine phenotype was not considered. Seventy percent of these genes were underexpressed in malignant compared to benign tumors. Similarly, 89% of genes were underexpressed in malignant primary tumors compared to benign tumors, suggesting that malignant potential is largely characterized by a less-differentiated pattern of gene expression. The present database of differentially expressed genes provides a unique resource for mapping the pathways leading to malignancy and for establishing new targets for treatment and diagnostic and prognostic markers of malignant disease. The database may also be useful for examining mechanisms of tumorigenesis and genotype–phenotype relationships. Further progress on the basis of this database can be made from follow-up confirmatory studies, application of bioinformatics approaches for data mining and pathway analyses, testing in pheochromocytoma cell culture and animal model systems, and retrospective and prospective studies of diagnostic markers. PMID:17102123

Distinguishing prognostic and predictive biomarkers: An information theoretic approach.

PubMed

Sechidis, Konstantinos; Papangelou, Konstantinos; Metcalfe, Paul D; Svensson, David; Weatherall, James; Brown, Gavin

2018-05-02

The identification of biomarkers to support decision-making is central to personalised medicine, in both clinical and research scenarios. The challenge can be seen in two halves: identifying predictive markers, which guide the development/use of tailored therapies; and identifying prognostic markers, which guide other aspects of care and clinical trial planning, i.e. prognostic markers can be considered as covariates for stratification. Mistakenly assuming a biomarker to be predictive, when it is in fact largely prognostic (and vice-versa) is highly undesirable, and can result in financial, ethical and personal consequences. We present a framework for data-driven ranking of biomarkers on their prognostic/predictive strength, using a novel information theoretic method. This approach provides a natural algebra to discuss and quantify the individual predictive and prognostic strength, in a self-consistent mathematical framework. Our contribution is a novel procedure, INFO+, which naturally distinguishes the prognostic vs predictive role of each biomarker and handles higher order interactions. In a comprehensive empirical evaluation INFO+ outperforms more complex methods, most notably when noise factors dominate, and biomarkers are likely to be falsely identified as predictive, when in fact they are just strongly prognostic. Furthermore, we show that our methods can be 1-3 orders of magnitude faster than competitors, making it useful for biomarker discovery in 'big data' scenarios. Finally, we apply our methods to identify predictive biomarkers on two real clinical trials, and introduce a new graphical representation that provides greater insight into the prognostic and predictive strength of each biomarker. R implementations of the suggested methods are available at https://github.com/sechidis. konstantinos.sechidis@manchester.ac.uk. Supplementary data are available at Bioinformatics online.

Anomalies in Network Bridges Involved in Bile Acid Metabolism Predict Outcomes of Colorectal Cancer Patients

PubMed Central

Yoon, Seyeol; Lee, Jae W.; Lee, Doheon

2014-01-01

Biomarkers prognostic for colorectal cancer (CRC) would be highly desirable in clinical practice. Proteins that regulate bile acid (BA) homeostasis, by linking metabolic sensors and metabolic enzymes, also called bridge proteins, may be reliable prognostic biomarkers for CRC. Based on a devised metric, “bridgeness,” we identified bridge proteins involved in the regulation of BA homeostasis and identified their prognostic potentials. The expression patterns of these bridge proteins could distinguish between normal and diseased tissues, suggesting that these proteins are associated with CRC pathogenesis. Using a supervised classification system, we found that these bridge proteins were reproducibly prognostic, with high prognostic ability compared to other known markers. PMID:25259881

Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) Study. Sarcoidosis Protocol.

PubMed

Moller, David R; Koth, Laura L; Maier, Lisa A; Morris, Alison; Drake, Wonder; Rossman, Milton; Leader, Joseph K; Collman, Ronald G; Hamzeh, Nabeel; Sweiss, Nadera J; Zhang, Yingze; O'Neal, Scott; Senior, Robert M; Becich, Michael; Hochheiser, Harry S; Kaminski, Naftali; Wisniewski, Stephen R; Gibson, Kevin F

2015-10-01

Sarcoidosis is a systemic disease characterized by noncaseating granulomatous inflammation with tremendous clinical heterogeneity and uncertain pathobiology and lacking in clinically useful biomarkers. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study is an observational cohort study designed to explore the role of the lung microbiome and genome in these two diseases. This article describes the design and rationale for the GRADS study sarcoidosis protocol. The study addresses the hypothesis that distinct patterns in the lung microbiome are characteristic of sarcoidosis phenotypes and are reflected in changes in systemic inflammatory responses as measured by peripheral blood changes in gene transcription. The goal is to enroll 400 participants, with a minimum of 35 in each of 9 clinical phenotype subgroups prioritized by their clinical relevance to understanding of the pathobiology and clinical heterogeneity of sarcoidosis. Participants with a confirmed diagnosis of sarcoidosis undergo a baseline visit with self-administered questionnaires, chest computed tomography, pulmonary function tests, and blood and urine testing. A research or clinical bronchoscopy with a research bronchoalveolar lavage will be performed to obtain samples for genomic and microbiome analyses. Comparisons will be made by blood genomic analysis and with clinical phenotypic variables. A 6-month follow-up visit is planned to assess each participant's clinical course. By the use of an integrative approach to the analysis of the microbiome and genome in selected clinical phenotypes, the GRADS study is powerfully positioned to inform and direct studies on the pathobiology of sarcoidosis, identify diagnostic or prognostic biomarkers, and provide novel molecular phenotypes that could lead to improved personalized approaches to therapy for sarcoidosis.

Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) Study. Sarcoidosis Protocol

PubMed Central

Koth, Laura L.; Maier, Lisa A.; Morris, Alison; Drake, Wonder; Rossman, Milton; Leader, Joseph K.; Collman, Ronald G.; Hamzeh, Nabeel; Sweiss, Nadera J.; Zhang, Yingze; O’Neal, Scott; Senior, Robert M.; Becich, Michael; Hochheiser, Harry S.; Kaminski, Naftali; Wisniewski, Stephen R.; Gibson, Kevin F.

2015-01-01

Sarcoidosis is a systemic disease characterized by noncaseating granulomatous inflammation with tremendous clinical heterogeneity and uncertain pathobiology and lacking in clinically useful biomarkers. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study is an observational cohort study designed to explore the role of the lung microbiome and genome in these two diseases. This article describes the design and rationale for the GRADS study sarcoidosis protocol. The study addresses the hypothesis that distinct patterns in the lung microbiome are characteristic of sarcoidosis phenotypes and are reflected in changes in systemic inflammatory responses as measured by peripheral blood changes in gene transcription. The goal is to enroll 400 participants, with a minimum of 35 in each of 9 clinical phenotype subgroups prioritized by their clinical relevance to understanding of the pathobiology and clinical heterogeneity of sarcoidosis. Participants with a confirmed diagnosis of sarcoidosis undergo a baseline visit with self-administered questionnaires, chest computed tomography, pulmonary function tests, and blood and urine testing. A research or clinical bronchoscopy with a research bronchoalveolar lavage will be performed to obtain samples for genomic and microbiome analyses. Comparisons will be made by blood genomic analysis and with clinical phenotypic variables. A 6-month follow-up visit is planned to assess each participant’s clinical course. By the use of an integrative approach to the analysis of the microbiome and genome in selected clinical phenotypes, the GRADS study is powerfully positioned to inform and direct studies on the pathobiology of sarcoidosis, identify diagnostic or prognostic biomarkers, and provide novel molecular phenotypes that could lead to improved personalized approaches to therapy for sarcoidosis. PMID:26193069

Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

PubMed

Tatton-Brown, Katrina; Murray, Anne; Hanks, Sandra; Douglas, Jenny; Armstrong, Ruth; Banka, Siddharth; Bird, Lynne M; Clericuzio, Carol L; Cormier-Daire, Valerie; Cushing, Tom; Flinter, Frances; Jacquemont, Marie-Line; Joss, Shelagh; Kinning, Esther; Lynch, Sally Ann; Magee, Alex; McConnell, Vivienne; Medeira, Ana; Ozono, Keiichi; Patton, Michael; Rankin, Julia; Shears, Debbie; Simon, Marleen; Splitt, Miranda; Strenger, Volker; Stuurman, Kyra; Taylor, Clare; Titheradge, Hannah; Van Maldergem, Lionel; Temple, I Karen; Cole, Trevor; Seal, Sheila; Rahman, Nazneen

2013-12-01

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve. © 2013 Wiley Periodicals, Inc.

A Syst-OMICS Approach to Ensuring Food Safety and Reducing the Economic Burden of Salmonellosis.

PubMed

Emond-Rheault, Jean-Guillaume; Jeukens, Julie; Freschi, Luca; Kukavica-Ibrulj, Irena; Boyle, Brian; Dupont, Marie-Josée; Colavecchio, Anna; Barrere, Virginie; Cadieux, Brigitte; Arya, Gitanjali; Bekal, Sadjia; Berry, Chrystal; Burnett, Elton; Cavestri, Camille; Chapin, Travis K; Crouse, Alanna; Daigle, France; Danyluk, Michelle D; Delaquis, Pascal; Dewar, Ken; Doualla-Bell, Florence; Fliss, Ismail; Fong, Karen; Fournier, Eric; Franz, Eelco; Garduno, Rafael; Gill, Alexander; Gruenheid, Samantha; Harris, Linda; Huang, Carol B; Huang, Hongsheng; Johnson, Roger; Joly, Yann; Kerhoas, Maud; Kong, Nguyet; Lapointe, Gisèle; Larivière, Line; Loignon, Stéphanie; Malo, Danielle; Moineau, Sylvain; Mottawea, Walid; Mukhopadhyay, Kakali; Nadon, Céline; Nash, John; Ngueng Feze, Ida; Ogunremi, Dele; Perets, Ann; Pilar, Ana V; Reimer, Aleisha R; Robertson, James; Rohde, John; Sanderson, Kenneth E; Song, Lingqiao; Stephan, Roger; Tamber, Sandeep; Thomassin, Paul; Tremblay, Denise; Usongo, Valentine; Vincent, Caroline; Wang, Siyun; Weadge, Joel T; Wiedmann, Martin; Wijnands, Lucas; Wilson, Emily D; Wittum, Thomas; Yoshida, Catherine; Youfsi, Khadija; Zhu, Lei; Weimer, Bart C; Goodridge, Lawrence; Levesque, Roger C

2017-01-01

The Salmonella Syst-OMICS consortium is sequencing 4,500 Salmonella genomes and building an analysis pipeline for the study of Salmonella genome evolution, antibiotic resistance and virulence genes. Metadata, including phenotypic as well as genomic data, for isolates of the collection are provided through the Salmonella Foodborne Syst-OMICS database (SalFoS), at https://salfos.ibis.ulaval.ca/. Here, we present our strategy and the analysis of the first 3,377 genomes. Our data will be used to draw potential links between strains found in fresh produce, humans, animals and the environment. The ultimate goals are to understand how Salmonella evolves over time, improve the accuracy of diagnostic methods, develop control methods in the field, and identify prognostic markers for evidence-based decisions in epidemiology and surveillance.

PROGNOSTIC VALUE OF SHAPE-DESCRIPTIVE FACTORS FOR THE PROGRESSION OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

PubMed

Pfau, Maximilian; Lindner, Moritz; Goerdt, Lukas; Thiele, Sarah; Nadal, Jennifer; Schmid, Matthias; Schmitz-Valckenberg, Steffen; Sadda, SriniVas R; Holz, Frank G; Fleckenstein, Monika

2018-05-16

To systematically compare the prognostic value of multiple shape-descriptive factors in the natural course of the disease. A total of 296 eyes of 201 patients (female patients 130; mean age: 72.2 ± 13.08 years) with a median follow-up of 2.38 years from 2 prospective, noninterventional natural history studies (Fundus-Autofluorescence-in-Age-related-Macular-Degeneration [clinicaltrials.gov identifier NCT00393692], Directional-Spread-in-Geographic-Atrophy [NCT02051998]) were included in the analysis. Serial fundus autofluorescence images were annotated using semiautomated image analysis software to determine the lesion area, circularity, perimeter, and caliper diameters. These variables and the fundus autofluorescence phenotype were evaluated for prediction of the future square root progression rates using linear mixed-effects models. For the combined model, leave-one-out cross validation on patient level (Scenario 1: previously unknown patient) resulted in a goodness-to-fit (R value) of 0.244 and leave-one-out cross validation on visit level (Scenario 2: previous observation of the patient) in a R value of 0.391. This indicated that shape-descriptive factors could explain 24.4% of the variance in geographic atrophy progression in previously unknown patients and 39.1% in patients with previous observation. These findings confirm the relevance of shape-descriptive factors and previous progression as prognostic variables for geographic atrophy progression. However, a substantial part of the remaining variation in geographic atrophy progression seems to depend on other variables, some of which are visible in optical coherence tomography.

Independent Prognostic Factors for Acute Organophosphorus Pesticide Poisoning.

PubMed

Tang, Weidong; Ruan, Feng; Chen, Qi; Chen, Suping; Shao, Xuebo; Gao, Jianbo; Zhang, Mao

2016-07-01

Acute organophosphorus pesticide poisoning (AOPP) is becoming a significant problem and a potential cause of human mortality because of the abuse of organophosphate compounds. This study aims to determine the independent prognostic factors of AOPP by using multivariate logistic regression analysis. The clinical data for 71 subjects with AOPP admitted to our hospital were retrospectively analyzed. This information included the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, admission blood cholinesterase levels, 6-h post-admission blood cholinesterase levels, cholinesterase activity, blood pH, and other factors. Univariate analysis and multivariate logistic regression analyses were conducted to identify all prognostic factors and independent prognostic factors, respectively. A receiver operating characteristic curve was plotted to analyze the testing power of independent prognostic factors. Twelve of 71 subjects died. Admission blood lactate levels, 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, blood pH, and APACHE II scores were identified as prognostic factors for AOPP according to the univariate analysis, whereas only 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, and blood pH were independent prognostic factors identified by multivariate logistic regression analysis. The receiver operating characteristic analysis suggested that post-admission 6-h lactate clearance rates were of moderate diagnostic value. High 6-h post-admission blood lactate levels, low blood pH, and low post-admission 6-h lactate clearance rates were independent prognostic factors identified by multivariate logistic regression analysis. Copyright © 2016 by Daedalus Enterprises.

SU-F-R-53: CT-Based Radiomics Analysis of Non-Small Cell Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huynh, E; Coroller, T; Narayan, V

Purpose: Stereotactic body radiation therapy (SBRT) is the standard of care for medically inoperable non-small cell lung cancer (NSCLC) patients and has demonstrated excellent local control and survival. However, some patients still develop distant metastases and local recurrence, and therefore, there is a clinical need to identify patients at high-risk of disease recurrence. The aim of the current study is to use a radiomics approach to identify imaging biomarkers, based on tumor phenotype, for clinical outcomes in SBRT patients. Methods: Radiomic features were extracted from free breathing computed tomography (CT) images of 113 Stage I-II NSCLC patients treated with SBRT.more » Their association to and prognostic performance for distant metastasis (DM), locoregional recurrence (LRR) and survival was assessed and compared with conventional features (tumor volume and diameter) and clinical parameters (e.g. performance status, overall stage). The prognostic performance was evaluated using the concordance index (CI). Multivariate model performance was evaluated using cross validation. All p-values were corrected for multiple testing using the false discovery rate. Results: Radiomic features were associated with DM (one feature), LRR (one feature) and survival (four features). Conventional features were only associated with survival and one clinical parameter was associated with LRR and survival. One radiomic feature was significantly prognostic for DM (CI=0.670, p<0.1 from random), while none of the conventional and clinical parameters were significant for DM. The multivariate radiomic model had a higher median CI (0.671) for DM than the conventional (0.618) and clinical models (0.617). Conclusion: Radiomic features have potential to be imaging biomarkers for clinical outcomes that conventional imaging metrics and clinical parameters cannot predict in SBRT patients, such as distant metastasis. Development of a radiomics biomarker that can identify patients at high-risk of recurrence could facilitate personalization of their treatment regimen for an optimized clinical outcome. R.M. had consulting interest with Amgen (ended in 2015).« less

Clinical presentations of 23 half-siblings from a mosaic neurofibromatosis type 1 sperm donor.

PubMed

Ejerskov, C; Farholt, S; Skovby, F; Vestergaard, E M; Haagerup, A

2016-03-01

The Danish sperm donor number 7042 has fathered several offspring with neurofibromatosis type 1 (NF1) worldwide. NF1 is caused by loss-of-function mutations in the NF1 gene and more than 1000 NF1 mutations are identified. Analysis of the donor sperm demonstrated gonosomal mosaicism with an intragenic deletion involving exons 15-29 in the NF1 gene. At the two Danish reference centres for NF1 patients, we evaluated 23 half-siblings from the donor. Nine were diagnosed with NF1. The severity grade of NF1 progressed from minimal to mild/moderate within 3 years of follow-up. The NF1 phenotype shows great variability in intra- and inter-family expressivity and to date only two NF1 genotype-phenotype correlations have been established. This rare possibility of a long-term follow-up of a cohort of half-siblings with NF1 makes further studies including phenotypic variability and search for modifier genes possible. To achieve this goal, we have initiated The International Donor 7042 NF1 Offspring Registry. Research facilitated via this registry may reveal important new knowledge of clinical characteristics and prognostics for the specific NF1 genotype and thereby contribute to future individualised targeted clinical follow-up and treatment. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer

PubMed Central

Bilen, Mehmet Asim; Hess, Kenneth R.; Broaddus, Russell R.; Kopetz, Scott; Wei, Chongjuan; Pagliaro, Lance C.; Karam, Jose A.; Ward, John F.; Wood, Christopher G.; Rao, Priya; Tu, Zachary H.; General, Rosale; Chen, Adrienne H.; Nieto, Yago L.; Yeung, Sai‐ching J.; Lin, Sue‐Hwa; Logothetis, Christopher J.; Pisters, Louis L.

2016-01-01

BACKGROUND Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. METHODS In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next‐generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. RESULTS Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac‐seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. CONCLUSIONS The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836–43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID:27018785

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer.

PubMed

Tu, Shi-Ming; Bilen, Mehmet Asim; Hess, Kenneth R; Broaddus, Russell R; Kopetz, Scott; Wei, Chongjuan; Pagliaro, Lance C; Karam, Jose A; Ward, John F; Wood, Christopher G; Rao, Priya; Tu, Zachary H; General, Rosale; Chen, Adrienne H; Nieto, Yago L; Yeung, Sai-Ching J; Lin, Sue-Hwa; Logothetis, Christopher J; Pisters, Louis L

2016-06-15

Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836-43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2016 American Cancer Society.

Variants of Brugada Syndrome and Early Repolarization Syndrome: An Expanded Concept of J-Wave Syndrome.

PubMed

Kim, Sung-Hwan; Nam, Gi-Byoung; Yun, Sung-Cheol; Choi, Hyung Oh; Choi, Kee-Joon; Joung, Boyoung; Pak, Hui-Nam; Lee, Moon-Hyoung; Kim, Sung Soon; Park, Seung-Jung; On, Young Keun; Kim, June Soo; Oh, Il-Young; Choi, Eue-Keun; Oh, Seil; Choi, Yun-Shik; Choi, Jong Il; Park, Sang Weon; Kim, Young-Hoon; Oh, Yong-Seog; Lee, Man Young; Lim, Hong Euy; Lee, Young-Soo; Cho, Yongkeun; Kim, Jun; Rhee, Kyoung-Suk; Lee, Dong-Il; Cho, Dae Kyoung; Kim, You-Ho

2017-02-01

The role of J-waves in the pathogenesis of ventricular fibrillation (VF) occurring in structurally normal hearts is important. We evaluated 127 patients who received an implantable cardioverter-defibrillator (ICD) for Brugada syndrome (BS, n = 53), early repolarization syndrome (ERS, n = 24), and patients with unknown or deferred diagnosis (n = 50). Electrocardiography (ECG), clinical characteristics, and ICD data were analyzed. J-waves were found in 27/50 patients with VF of unknown/deferred diagnosis. The J-waves were reminiscent of those seen in BS or ERS, and this subgroup of patients was termed variants of ERS and BS (VEB). In 12 VEB patients, the J/ST/T-wave morphology was coved, although amplitudes were <0.2 mV. In 15 patients, noncoved-type J/ST/T-waves were present in the right precordial leads. In the remaining 23 patients, no J-waves were identified. VEB patients exhibited clinical characteristics similar to those of BS and ERS patients. Phenotypic transition and overlap were observed among patients with BS, ERS, and VEB. Twelve patients with BS had background inferolateral ER, while five ERS patients showed prominent right precordial J-waves. Patients with this transient phenotype overlap showed a significantly lower shock-free survival than the rest of the study patients. VEB patients demonstrate ECG phenotype similar to but distinct from those of BS and ERS. The spectral nature of J-wave morphology/distribution and phenotypic transition/overlap suggest a common pathophysiologic background in patients with VEB, BS, and ERS. Prognostic implication of these ECG variations requires further investigation. © 2016 Wiley Periodicals, Inc.

Prognosis Research Strategy (PROGRESS) 2: prognostic factor research.

PubMed

Riley, Richard D; Hayden, Jill A; Steyerberg, Ewout W; Moons, Karel G M; Abrams, Keith; Kyzas, Panayiotis A; Malats, Núria; Briggs, Andrew; Schroter, Sara; Altman, Douglas G; Hemingway, Harry

2013-01-01

Prognostic factor research aims to identify factors associated with subsequent clinical outcome in people with a particular disease or health condition. In this article, the second in the PROGRESS series, the authors discuss the role of prognostic factors in current clinical practice, randomised trials, and developing new interventions, and explain why and how prognostic factor research should be improved.

Extramural vascular invasion and response to neoadjuvant chemoradiotherapy in rectal cancer: Influence of the CpG island methylator phenotype

PubMed Central

Williamson, Jeremy Stuart; Jones, Huw Geraint; Williams, Namor; Griffiths, Anthony Paul; Jenkins, Gareth; Beynon, John; Harris, Dean Anthony

2017-01-01

AIM To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer. METHODS Patients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status (high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed. RESULTS There were 160 patients analysed with a median follow-up time of 46.4 mo. Twenty-one (13%) patients demonstrated high levels of CIMP methylation (CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion (EMVI) compared with CIMP-L [8/21 (38%) vs 15/99 (15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival (P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation (P = 0.01). There were 14 (9%) patients with a pathological complete response (pCR) compared to 116 (73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant (P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced “T” stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence. CONCLUSION We report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination. PMID:28567185

Extramural vascular invasion and response to neoadjuvant chemoradiotherapy in rectal cancer: Influence of the CpG island methylator phenotype.

PubMed

Williamson, Jeremy Stuart; Jones, Huw Geraint; Williams, Namor; Griffiths, Anthony Paul; Jenkins, Gareth; Beynon, John; Harris, Dean Anthony

2017-05-15

To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer. Patients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status (high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed. There were 160 patients analysed with a median follow-up time of 46.4 mo. Twenty-one (13%) patients demonstrated high levels of CIMP methylation (CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion (EMVI) compared with CIMP-L [8/21 (38%) vs 15/99 (15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival ( P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation ( P = 0.01). There were 14 (9%) patients with a pathological complete response (pCR) compared to 116 (73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant ( P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced "T" stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence. We report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination.

Doubt and belief in physicians' ability to prognosticate during critical illness: The perspective of surrogate decision makers

PubMed Central

Zier, Lucas S.; Burack, Jeffrey H.; Micco, Guy; Chipman, Anne K.; Frank, James A.; Luce, John M.; White, Douglas B.

2009-01-01

Objectives: Although discussing a prognosis is a duty of physicians caring for critically ill patients, little is known about surrogate decision-makers' beliefs about physicians' ability to prognosticate. We sought to determine: 1) surrogates' beliefs about whether physicians can accurately prognosticate for critically ill patients; and 2) how individuals use prognostic information in their role as surrogate decision-makers. Design, Setting, and Patients: Multicenter study in intensive care units of a public hospital, a tertiary care hospital, and a veterans' hospital. We conducted semistructured interviews with 50 surrogate decision-makers of critically ill patients. We analyzed the interview transcripts using grounded theory methods to inductively develop a framework to describe surrogates' beliefs about physicians' ability to prognosticate. Validation methods included triangulation by multidisciplinary analysis and member checking. Measurements and Main Results: Overall, 88% (44 of 50) of surrogates expressed doubt about physicians' ability to prognosticate for critically ill patients. Four distinct themes emerged that explained surrogates' doubts about prognostic accuracy: a belief that God could alter the course of the illness, a belief that predicting the future is inherently uncertain, prior experiences where physicians' prognostications were inaccurate, and experiences with prognostication during the patient's intensive care unit stay. Participants also identified several factors that led to belief in physicians' prognostications, such as receiving similar prognostic estimates from multiple physicians and prior experiences with accurate prognostication. Surrogates' doubts about prognostic accuracy did not prevent them from wanting prognostic information. Instead, most surrogate decision-makers view physicians' prognostications as rough estimates that are valuable in informing decisions, but are not determinative. Surrogates identified the act of prognostic disclosure as a key step in preparing emotionally and practically for the possibility that a patient may not survive. Conclusions: Although many surrogate decision-makers harbor some doubt about the accuracy of physicians' prognostications, they highly value discussions about prognosis and use the information for multiple purposes. (Crit Care Med 2008; 36: 2341–2347) PMID:18596630

Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

PubMed Central

Bierie, Brian; Pierce, Sarah E.; Kroeger, Cornelia; Stover, Daniel G.; Pattabiraman, Diwakar R.; Thiru, Prathapan; Liu Donaher, Joana; Reinhardt, Ferenc; Chaffer, Christine L.; Keckesova, Zuzana; Weinberg, Robert A.

2017-01-01

Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin-β4 (ITGB4), can be used to enable stratification of mesenchymal-like triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4+ cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival. Mechanistically, we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63α (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC. PMID:28270621

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

PubMed Central

Hopp, Katharina; Cogal, Andrea G.; Bergstralh, Eric J.; Seide, Barbara M.; Olson, Julie B.; Meek, Alicia M.; Lieske, John C.; Milliner, Dawn S.

2015-01-01

Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial. PMID:25644115

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria.

PubMed

Hopp, Katharina; Cogal, Andrea G; Bergstralh, Eric J; Seide, Barbara M; Olson, Julie B; Meek, Alicia M; Lieske, John C; Milliner, Dawn S; Harris, Peter C

2015-10-01

Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial. Copyright © 2015 by the American Society of Nephrology.

Prognostication in Philadelphia Chromosome Negative Myeloproliferative Neoplasms: a Review of the Recent Literature.

PubMed

Zhou, Amy; Afzal, Amber; Oh, Stephen T

2017-10-01

The prognosis for patients with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is highly variable. All Ph-negative MPNs carry an increased risk for thrombotic complications, bleeding, and leukemic transformation. Several clinical, biological, and molecular prognostic factors have been identified in recent years, which provide important information in guiding management of patients with Ph-negative MPNs. In this review, we critically evaluate the recent published literature and discuss important new developments in clinical and molecular factors that impact survival, disease transformation, and thrombosis in patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Recent studies have identified several clinical factors and non-driver mutations to have prognostic impact on Ph-negative MPNs independent of conventional risk stratification and prognostic models. In polycythemia vera (PV), leukocytosis, abnormal karyotype, phlebotomy requirement on hydroxyurea, increased bone marrow fibrosis, and mutations in ASXL1, SRSF2, and IDH2 were identified as additional adverse prognostic factors. In essential thrombocythemia (ET), JAK2 V617F mutation, splenomegaly, and mutations in SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2 were found to be additional negative prognostic factors. Bone marrow fibrosis and mutations in ASXL1, SRSF2, EZH2, and IDH1/2 have been found to be additional prognostic factors in primary myelofibrosis (PMF). CALR mutations appear to be a favorable prognostic factor in PMF, which has not been clearly demonstrated in ET. The prognosis for patients with PV, ET, and PMF is dependent upon the presence or absence of several clinical, biological, and molecular risk factors. The significance of additional risk factors identified in these recent studies will need further validation in prospective studies to determine how they may be best utilized in the management of these disorders.

Copy number increase of ACTN4 is a prognostic indicator in salivary gland carcinoma

PubMed Central

Watabe, Yukio; Mori, Taisuke; Yoshimoto, Seiichi; Nomura, Takeshi; Shibahara, Takahiko; Yamada, Tesshi; Honda, Kazufumi

2014-01-01

Copy number increase (CNI) of ACTN4 has been associated with poor prognosis and metastatic phenotypes in various human carcinomas. To identify a novel prognostic factor for salivary gland carcinoma, we investigated the copy number of ACTN4. We evaluated DNA copy number of ACTN4 in 58 patients with salivary gland carcinoma by using fluorescent in situ hybridization (FISH). CNI of ACTN4 was recognized in 14 of 58 patients (24.1%) with salivary gland carcinoma. The cases with CNI of ACTN4 were closely associated with histological grade (P = 0.047) and vascular invasion (P = 0.033). The patients with CNI of ACTN4 had a significantly worse prognosis than the patients with normal copy number of ACTN4 (P = 0.0005 log-rank test). Univariate analysis by the Cox proportional hazards model showed that histological grade, vascular invasion, and CNI of ACTN4 were independent risk factors for cancer death. Vascular invasion (hazard ratio [HR]: 7.46; 95% confidence interval [CI]: 1.98–28.06) and CNI of ACTN4 (HR: 3.23; 95% CI: 1.08–9.68) remained as risk factors for cancer death in multivariate analysis. Thus, CNI of ACTN4 is a novel indicator for an unfavorable outcome in patients with salivary gland carcinoma. PMID:24574362

Historic, clinical, and prognostic features of epileptic encephalopathies caused by CDKL5 mutations.

PubMed

Moseley, Brian D; Dhamija, Radhika; Wirrell, Elaine C; Nickels, Katherine C

2012-02-01

Mutations within the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene are important causes of early-onset epileptic encephalopathies. We sought to determine the historic, clinical, and prognostic features of epilepsy secondary to CDKL5 mutations. We performed retrospective chart reviews of children at our institution with epilepsy and CDKL5 mutations. Six children were identified. One manifested a deletion in exons 10-15 of the CDKL5 gene, another manifested a single base-pair duplication in exon 3, and the rest manifested base-pair exchanges. The mean age of seizure onset was 1.8 months (range, 1-3 months). Although the majority (4/6, 67%) presented with partial-onset seizures, all children developed infantile spasms. All children demonstrated developmental delay and visual impairment. Although such mutations are X-linked, two children were boys. They did not present with more severe phenotypes than their female counterparts. Despite trials of antiepileptic drugs (mean, 5; range, 3-7), steroids/adrenocorticotropic hormone (4/6; 67%), and the ketogenic diet (6/6; 100%), all children manifested refractory seizures at last follow-up. Although no treatment eliminated seizures, topiramate, vigabatrin, and the ketogenic diet were most helpful at reducing seizure frequency. Copyright © 2012 Elsevier Inc. All rights reserved.

Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Upregulation of antioxidant genes correlates with regression of melanoma malignancy and with malignant progression when downregulated.

PubMed

Bracalente, Candelaria; Ibañez, Irene L; Berenstein, Ariel; Notcovich, Cintia; Cerda, María B; Klamt, Fabio; Chernomoretz, Ariel; Durán, Hebe

2016-07-05

Reactive oxygen species (ROS) are implicated in tumor transformation. The antioxidant system (AOS) protects cells from ROS damage. However, it is also hijacked by cancers cells to proliferate within the tumor. Thus, identifying proteins altered by redox imbalance in cancer cells is an attractive prognostic and therapeutic tool. Gene expression microarrays in A375 melanoma cells with different ROS levels after overexpressing catalase were performed. Dissimilar phenotypes by differential compensation to hydrogen peroxide scavenging were generated. The melanotic A375-A7 (A7) upregulated TYRP1, CNTN1 and UCHL1 promoting melanogenesis. The metastatic A375-G10 (G10) downregulated MTSS1 and TIAM1, proteins absent in metastasis. Moreover, differential coexpression of AOS genes (EPHX2, GSTM3, MGST1, MSRA, TXNRD3, MGST3 and GSR) was found in A7 and G10. Their increase in A7 improved its AOS ability and therefore, oxidative stress response, resembling less aggressive tumor cells. Meanwhile, their decrease in G10 revealed a disruption in the AOS and therefore, enhanced its metastatic capacity.These gene signatures, not only bring new insights into the physiopathology of melanoma, but also could be relevant in clinical prognostic to classify between non aggressive and metastatic melanomas.

Tumour Cell Heterogeneity

PubMed Central

Gay, Laura; Baker, Ann-Marie; Graham, Trevor A.

2016-01-01

The population of cells that make up a cancer are manifestly heterogeneous at the genetic, epigenetic, and phenotypic levels. In this mini-review, we summarise the extent of intra-tumour heterogeneity (ITH) across human malignancies, review the mechanisms that are responsible for generating and maintaining ITH, and discuss the ramifications and opportunities that ITH presents for cancer prognostication and treatment. PMID:26973786

Infant Attentional Behaviours as Prognostic Indicators in Cornelia-de-Lange Syndrome

ERIC Educational Resources Information Center

Sarimski, Klaus

2007-01-01

Background: Cornelia-de-Lange syndrome is a rare congenital syndrome with poor social relatedness as one of several characteristics of its behavioural phenotype. Methods: Video observations were collected from seven children in their first year of life and again with age 2-4 years. Data were analysed for distribution of object-related and social…

If the skull fits: magnetic resonance imaging and microcomputed tomography for combined analysis of brain and skull phenotypes in the mouse

PubMed Central

Blank, Marissa C.; Roman, Brian B.; Henkelman, R. Mark; Millen, Kathleen J.

2012-01-01

The mammalian brain and skull develop concurrently in a coordinated manner, consistently producing a brain and skull that fit tightly together. It is common that abnormalities in one are associated with related abnormalities in the other. However, this is not always the case. A complete characterization of the relationship between brain and skull phenotypes is necessary to understand the mechanisms that cause them to be coordinated or divergent and to provide perspective on the potential diagnostic or prognostic significance of brain and skull phenotypes. We demonstrate the combined use of magnetic resonance imaging and microcomputed tomography for analysis of brain and skull phenotypes in the mouse. Co-registration of brain and skull images allows comparison of the relationship between phenotypes in the brain and those in the skull. We observe a close fit between the brain and skull of two genetic mouse models that both show abnormal brain and skull phenotypes. Application of these three-dimensional image analyses in a broader range of mouse mutants will provide a map of the relationships between brain and skull phenotypes generally and allow characterization of patterns of similarities and differences. PMID:22947655

Deletion of 1p32-p36 is the most frequent genetic change and poor prognostic marker in adenoid cystic carcinoma of the salivary glands.

PubMed

Rao, Pulivarthi H; Roberts, Diana; Zhao, Yi-Jue; Bell, Diana; Harris, Charles P; Weber, Randal S; El-Naggar, Adel K

2008-08-15

Adenoid cystic carcinoma (ACC) is a relatively uncommon salivary gland malignancy known for its protean phenotypic features and pernicious clinical behavior. Currently, no effective therapy is available for patients with advanced nonresectable, recurrent, and/or metastatic disease. The purpose of this study is to identify prognostic factors other than tumor stage that can be used to predict the outcome of the patients with ACC. We used comparative genomic hybridization (CGH) to identify copy number aberrations in 53 primary ACCs. Array CGH and fluorescence in situ hybridization analysis was used to validate CGH results on selected cases. We correlated these copy number aberrations with clinicopathologic factors using Pearson's chi2 or by the two-tailed Fisher exact test. The disease-specific survival and disease-free intervals were generated by the Kaplan-Meier product limit method. Chromosomal losses (n = 134) were more frequent than gains (n = 74). The most frequent genetic change was the loss of 1p32-p36 in 44% of the cases followed by 6q23-q27, and 12q12-q14. The most frequently gained chromosomal regions were 8 and 18. Of the chromosomal aberrations, loss of 1p32-p36 was the only abnormality significantly associated with patient's outcome. This study, for the first time, identifies loss of 1p32-p36 as a significant aberration in ACC. Molecular characterization of 1p32-36 region using the available genomic technologies may lead to the identification of new genes critical to the development of novel therapeutic targets for this disease copy number aberration.

Cytogenetic prognostication within medulloblastoma subgroups.

PubMed

Shih, David J H; Northcott, Paul A; Remke, Marc; Korshunov, Andrey; Ramaswamy, Vijay; Kool, Marcel; Luu, Betty; Yao, Yuan; Wang, Xin; Dubuc, Adrian M; Garzia, Livia; Peacock, John; Mack, Stephen C; Wu, Xiaochong; Rolider, Adi; Morrissy, A Sorana; Cavalli, Florence M G; Jones, David T W; Zitterbart, Karel; Faria, Claudia C; Schüller, Ulrich; Kren, Leos; Kumabe, Toshihiro; Tominaga, Teiji; Shin Ra, Young; Garami, Miklós; Hauser, Peter; Chan, Jennifer A; Robinson, Shenandoah; Bognár, László; Klekner, Almos; Saad, Ali G; Liau, Linda M; Albrecht, Steffen; Fontebasso, Adam; Cinalli, Giuseppe; De Antonellis, Pasqualino; Zollo, Massimo; Cooper, Michael K; Thompson, Reid C; Bailey, Simon; Lindsey, Janet C; Di Rocco, Concezio; Massimi, Luca; Michiels, Erna M C; Scherer, Stephen W; Phillips, Joanna J; Gupta, Nalin; Fan, Xing; Muraszko, Karin M; Vibhakar, Rajeev; Eberhart, Charles G; Fouladi, Maryam; Lach, Boleslaw; Jung, Shin; Wechsler-Reya, Robert J; Fèvre-Montange, Michelle; Jouvet, Anne; Jabado, Nada; Pollack, Ian F; Weiss, William A; Lee, Ji-Yeoun; Cho, Byung-Kyu; Kim, Seung-Ki; Wang, Kyu-Chang; Leonard, Jeffrey R; Rubin, Joshua B; de Torres, Carmen; Lavarino, Cinzia; Mora, Jaume; Cho, Yoon-Jae; Tabori, Uri; Olson, James M; Gajjar, Amar; Packer, Roger J; Rutkowski, Stefan; Pomeroy, Scott L; French, Pim J; Kloosterhof, Nanne K; Kros, Johan M; Van Meir, Erwin G; Clifford, Steven C; Bourdeaut, Franck; Delattre, Olivier; Doz, François F; Hawkins, Cynthia E; Malkin, David; Grajkowska, Wieslawa A; Perek-Polnik, Marta; Bouffet, Eric; Rutka, James T; Pfister, Stefan M; Taylor, Michael D

2014-03-20

Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

Cytogenetic Prognostication Within Medulloblastoma Subgroups

PubMed Central

Shih, David J.H.; Northcott, Paul A.; Remke, Marc; Korshunov, Andrey; Ramaswamy, Vijay; Kool, Marcel; Luu, Betty; Yao, Yuan; Wang, Xin; Dubuc, Adrian M.; Garzia, Livia; Peacock, John; Mack, Stephen C.; Wu, Xiaochong; Rolider, Adi; Morrissy, A. Sorana; Cavalli, Florence M.G.; Jones, David T.W.; Zitterbart, Karel; Faria, Claudia C.; Schüller, Ulrich; Kren, Leos; Kumabe, Toshihiro; Tominaga, Teiji; Shin Ra, Young; Garami, Miklós; Hauser, Peter; Chan, Jennifer A.; Robinson, Shenandoah; Bognár, László; Klekner, Almos; Saad, Ali G.; Liau, Linda M.; Albrecht, Steffen; Fontebasso, Adam; Cinalli, Giuseppe; De Antonellis, Pasqualino; Zollo, Massimo; Cooper, Michael K.; Thompson, Reid C.; Bailey, Simon; Lindsey, Janet C.; Di Rocco, Concezio; Massimi, Luca; Michiels, Erna M.C.; Scherer, Stephen W.; Phillips, Joanna J.; Gupta, Nalin; Fan, Xing; Muraszko, Karin M.; Vibhakar, Rajeev; Eberhart, Charles G.; Fouladi, Maryam; Lach, Boleslaw; Jung, Shin; Wechsler-Reya, Robert J.; Fèvre-Montange, Michelle; Jouvet, Anne; Jabado, Nada; Pollack, Ian F.; Weiss, William A.; Lee, Ji-Yeoun; Cho, Byung-Kyu; Kim, Seung-Ki; Wang, Kyu-Chang; Leonard, Jeffrey R.; Rubin, Joshua B.; de Torres, Carmen; Lavarino, Cinzia; Mora, Jaume; Cho, Yoon-Jae; Tabori, Uri; Olson, James M.; Gajjar, Amar; Packer, Roger J.; Rutkowski, Stefan; Pomeroy, Scott L.; French, Pim J.; Kloosterhof, Nanne K.; Kros, Johan M.; Van Meir, Erwin G.; Clifford, Steven C.; Bourdeaut, Franck; Delattre, Olivier; Doz, François F.; Hawkins, Cynthia E.; Malkin, David; Grajkowska, Wieslawa A.; Perek-Polnik, Marta; Bouffet, Eric; Rutka, James T.; Pfister, Stefan M.; Taylor, Michael D.

2014-01-01

Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials. PMID:24493713

Prognostic significance of monocarboxylate transporter expression in oral cavity tumors

PubMed Central

Simões-Sousa, Susana; Granja, Sara; Pinheiro, Céline; Fernandes, Daniela; Longatto-Filho, Adhemar; Laus, Ana Carolina; Alves, Cira Danielle Casado; Suárez-Peñaranda, J. M.; Pérez-Sayáns, Mario; Lopes Carvalho, Andre; Schmitt, Fernando C.; García-García, Abel; Baltazar, Fatima

2016-01-01

ABSTRACT Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer. The majority of patients present advanced stage disease and has poor survival. Therefore, it is imperative to search for new biomarkers and new alternative and effective treatment options. Most cancer cells rely on aerobic glycolysis to generate energy and metabolic intermediates. This phenotype is a hallmark of cancer, characterized by an increase in glucose consumption and production of high amounts of lactate. Consequently, cancer cells need to up-regulate many proteins and enzymes related with the glycolytic metabolism. Thus, the aim of this study was to characterize metabolic phenotype of oral cavity cancers (OCC) by assessing the expression pattern of monocarboxylate transporters (MCTs) 1, 2 and 4 and other proteins related with the glycolytic phenotype. Material and Methods: We evaluated the immunohistochemical expression of MCT1, MCT4, CD147, GLUT1 and CAIX in 135 human samples of OCC and investigated the correlation with clinicopathological parameters and the possible association with prognosis. Results: We observed that all proteins analyzed presented significantly higher plasma membrane expression in neoplastic compared to non-neoplastic samples. MCT4 was significantly associated with T-stage and advanced tumoral stage, while CD147 was significantly correlated with histologic differentiation. Interestingly, tumors expressing both MCT1 and MCT4 but negative for MCT2 were associated with shorter overall survival. Conclusion: Overexpression of MCT1/4, CD147, GLUT1 and CAIX, supports previous findings of metabolic reprograming in OCC, warranting future studies to explore the hyper-glycolytic phenotype of these tumors. Importantly, MCT expression revealed to have a prognostic value in OCC survival. PMID:27232157

Ribosomal Proteins RPS11 and RPS20, Two Stress-Response Markers of Glioblastoma Stem Cells, Are Novel Predictors of Poor Prognosis in Glioblastoma Patients

PubMed Central

Yang, Shuai; Tso, Jonathan L.; Menjivar, Jimmy C.; Wei, Bowen; Lucey, Gregory M.; Mareninov, Sergey; Chen, Zugen; Liau, Linda M.; Lai, Albert; Nelson, Stanley F.; Cloughesy, Timothy F.; Tso, Cho-Lea

2015-01-01

Glioblastoma stem cells (GSC) co-exhibiting a tumor-initiating capacity and a radio-chemoresistant phenotype, are a compelling cell model for explaining tumor recurrence. We have previously characterized patient-derived, treatment-resistant GSC clones (TRGC) that survived radiochemotherapy. Compared to glucose-dependent, treatment-sensitive GSC clones (TSGC), TRGC exhibited reduced glucose dependence that favor the fatty acid oxidation pathway as their energy source. Using comparative genome-wide transcriptome analysis, a series of defense signatures associated with TRGC survival were identified and verified by siRNA-based gene knockdown experiments that led to loss of cell integrity. In this study, we investigate the prognostic value of defense signatures in glioblastoma (GBM) patients using gene expression analysis with Probeset Analyzer (131 GBM) and The Cancer Genome Atlas (TCGA) data, and protein expression with a tissue microarray (50 GBM), yielding the first TRGC-derived prognostic biomarkers for GBM patients. Ribosomal protein S11 (RPS11), RPS20, individually and together, consistently predicted poor survival of newly diagnosed primary GBM tumors when overexpressed at the RNA or protein level [RPS11: Hazard Ratio (HR) = 11.5, p<0.001; RPS20: HR = 4.5, p = 0.03; RPS11+RPS20: HR = 17.99, p = 0.001]. The prognostic significance of RPS11 and RPS20 was further supported by whole tissue section RPS11 immunostaining (27 GBM; HR = 4.05, p = 0.01) and TCGA gene expression data (578 primary GBM; RPS11: HR = 1.19, p = 0.06; RPS20: HR = 1.25, p = 0.02; RPS11+RPS20: HR = 1.43, p = 0.01). Moreover, tumors that exhibited unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) or wild-type isocitrate dehydrogenase 1 (IDH1) were associated with higher RPS11 expression levels [corr (IDH1, RPS11) = 0.64, p = 0.03); [corr (MGMT, RPS11) = 0.52, p = 0.04]. These data indicate that increased expression of RPS11 and RPS20 predicts shorter patient survival. The study also suggests that TRGC are clinically relevant cells that represent resistant tumorigenic clones from patient tumors and that their properties, at least in part, are reflected in poor-prognosis GBM. The screening of TRGC signatures may represent a novel alternative strategy for identifying new prognostic biomarkers. PMID:26506620

DGKI methylation status modulates the prognostic value of MGMT in glioblastoma patients treated with combined radio-chemotherapy with temozolomide.

PubMed

Etcheverry, Amandine; Aubry, Marc; Idbaih, Ahmed; Vauleon, Elodie; Marie, Yannick; Menei, Philippe; Boniface, Rachel; Figarella-Branger, Dominique; Karayan-Tapon, Lucie; Quillien, Veronique; Sanson, Marc; de Tayrac, Marie; Delattre, Jean-Yves; Mosser, Jean

2014-01-01

Consistently reported prognostic factors for glioblastoma (GBM) are age, extent of surgery, performance status, IDH1 mutational status, and MGMT promoter methylation status. We aimed to integrate biological and clinical prognostic factors into a nomogram intended to predict the survival time of an individual GBM patient treated with a standard regimen. In a previous study we showed that the methylation status of the DGKI promoter identified patients with MGMT-methylated tumors that responded poorly to the standard regimen. We further evaluated the potential prognostic value of DGKI methylation status. 399 patients with newly diagnosed GBM and treated with a standard regimen were retrospectively included in this study. Survival modelling was performed on two patient populations: intention-to-treat population of all included patients (population 1) and MGMT-methylated patients (population 2). Cox proportional hazard models were fitted to identify the main prognostic factors. A nomogram was developed for population 1. The prognostic value of DGKI promoter methylation status was evaluated on population 1 and population 2. The nomogram-based stratification of the cohort identified two risk groups (high/low) with significantly different median survival. We validated the prognostic value of DGKI methylation status for MGMT-methylated patients. We also demonstrated that the DGKI methylation status identified 22% of poorly responding patients in the low-risk group defined by the nomogram. Our results improve the conventional MGMT stratification of GBM patients receiving standard treatment. These results could help the interpretation of published or ongoing clinical trial outcomes and refine patient recruitment in the future.

Predicting cancer prognosis using interactive online tools: A systematic review and implications for cancer care providers

PubMed Central

Rabin, Borsika A.; Gaglio, Bridget; Sanders, Tristan; Nekhlyudov, Larissa; Dearing, James W.; Bull, Sheana; Glasgow, Russell E.; Marcus, Alfred

2013-01-01

Cancer prognosis is of keen interest for cancer patients, their caregivers and providers. Prognostic tools have been developed to guide patient-physician communication and decision-making. Given the proliferation of prognostic tools, it is timely to review existing online cancer prognostic tools and discuss implications for their use in clinical settings. Using a systematic approach, we searched the Internet, Medline, and consulted with experts to identify existing online prognostic tools. Each was reviewed for content and format. Twenty-two prognostic tools addressing 89 different cancers were identified. Tools primarily focused on prostate (n=11), colorectal (n=10), breast (n=8), and melanoma (n=6), though at least one tool was identified for most malignancies. The input variables for the tools included cancer characteristics (n=22), patient characteristics (n=18), and comorbidities (n=9). Effect of therapy on prognosis was included in 15 tools. The most common predicted outcome was cancer specific survival/mortality (n=17). Only a few tools (n=4) suggested patients as potential target users. A comprehensive repository of online prognostic tools was created to understand the state-of-the-art in prognostic tool availability and characteristics. Use of these tools may support communication and understanding about cancer prognosis. Dissemination, testing, refinement of existing, and development of new tools under different conditions are needed. PMID:23956026

Monogenic diabetes syndromes: Locus‐specific databases for Alström, Wolfram, and Thiamine‐responsive megaloblastic anemia

PubMed Central

Astuti, Dewi; Sabir, Ataf; Fulton, Piers; Zatyka, Malgorzata; Williams, Denise; Hardy, Carol; Milan, Gabriella; Favaretto, Francesca; Yu‐Wai‐Man, Patrick; Rohayem, Julia; López de Heredia, Miguel; Hershey, Tamara; Tranebjaerg, Lisbeth; Chen, Jian‐Hua; Chaussenot, Annabel; Nunes, Virginia; Marshall, Bess; McAfferty, Susan; Tillmann, Vallo; Maffei, Pietro; Paquis‐Flucklinger, Veronique; Geberhiwot, Tarekign; Mlynarski, Wojciech; Parkinson, Kay; Picard, Virginie; Bueno, Gema Esteban; Dias, Renuka; Arnold, Amy; Richens, Caitlin; Paisey, Richard; Urano, Fumihiko; Semple, Robert; Sinnott, Richard

2017-01-01

Abstract We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease‐associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine‐responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype–phenotype relations for the WFS1 gene. The presence of biallelic loss‐of‐function variants predicted Wolfram syndrome defined by insulin‐dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%–83%) and specificity of 92% (83%–97%). The presence of minor loss‐of‐function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%–100%]; specificity 78% [73%–82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next‐generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org. PMID:28432734

Next generation sequencing in women affected by nonsyndromic premature ovarian failure displays new potential causative genes and mutations.

PubMed

Fonseca, Dora Janeth; Patiño, Liliana Catherine; Suárez, Yohjana Carolina; de Jesús Rodríguez, Asid; Mateus, Heidi Eliana; Jiménez, Karen Marcela; Ortega-Recalde, Oscar; Díaz-Yamal, Ivonne; Laissue, Paul

2015-07-01

To identify new molecular actors involved in nonsyndromic premature ovarian failure (POF) etiology. This is a retrospective case-control cohort study. University research group and IVF medical center. Twelve women affected by nonsyndromic POF. The control group included 176 women whose menopause had occurred after age 50 and had no antecedents regarding gynecological disease. A further 345 women from the same ethnic origin (general population group) were also recruited to assess allele frequency for potentially deleterious sequence variants. Next generation sequencing (NGS), Sanger sequencing, and bioinformatics analysis. The complete coding regions of 70 candidate genes were massively sequenced, via NGS, in POF patients. Bioinformatics and genetics were used to confirm NGS results and to identify potential sequence variants related to the disease pathogenesis. We have identified mutations in two novel genes, ADAMTS19 and BMPR2, that are potentially related to POF origin. LHCGR mutations, which might have contributed to the phenotype, were also detected. We thus recommend NGS as a powerful tool for identifying new molecular actors in POF and for future diagnostic/prognostic purposes. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction

PubMed Central

Floras, John S.; Ponikowski, Piotr

2015-01-01

Cardiovascular autonomic imbalance, a cardinal phenotype of human heart failure, has adverse implications for symptoms during wakefulness and sleep; for cardiac, renal, and immune function; for exercise capacity; and for lifespan and mode of death. The objectives of this Clinical Review are to summarize current knowledge concerning mechanisms for disturbed parasympathetic and sympathetic circulatory control in heart failure with reduced ejection fraction and its clinical and prognostic implications; to demonstrate the patient-specific nature of abnormalities underlying this common phenotype; and to illustrate how such variation provides opportunities to improve or restore normal sympathetic/parasympathetic balance through personalized drug or device therapy. PMID:25975657

Genome-Wide Association Study of Metabolic Traits Reveals Novel Gene-Metabolite-Disease Links

PubMed Central

Nicholls, Andrew W.; Salek, Reza M.; Marques-Vidal, Pedro; Morya, Edgard; Sameshima, Koichi; Montoliu, Ivan; Da Silva, Laeticia; Collino, Sebastiano; Martin, François-Pierre; Rezzi, Serge; Steinbeck, Christoph; Waterworth, Dawn M.; Waeber, Gérard; Vollenweider, Peter; Beckmann, Jacques S.; Le Coutre, Johannes; Mooser, Vincent; Bergmann, Sven; Genick, Ulrich K.; Kutalik, Zoltán

2014-01-01

Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on 1H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10−8) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10−44) and lysine (rs8101881, P = 1.2×10−33), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers. PMID:24586186

Characterization of Desmoglein Expression in the Normal Prostatic Gland. Desmoglein 2 Is an Independent Prognostic Factor for Aggressive Prostate Cancer

PubMed Central

Barber, Alison G.; Castillo-Martin, Mireia; Bonal, Dennis M.; Rybicki, Benjamin A.; Christiano, Angela M.; Cordon-Cardo, Carlos

2014-01-01

Purpose The expression of desmogleins (DSGs), which are known to be crucial for establishing and maintaining the cell-cell adhesion required for tissue integrity, has been well characterized in the epidermis and hair follicle; however, their expression in other epithelial tissues such as prostate is poorly understood. Although downregulation of classical cadherins, such as E-cadherin, has been described in prostate cancer tissue samples, the expression of desmogleins has only been previously reported in prostate cancer cell lines. In this study we characterized desmoglein expression in normal prostate tissues, and further investigated whether Desmoglein 2 (DSG2) expression specifically can serve as a potential clinical prognostic factor for patients diagnosed with primary prostate cancer. Experimental Design We utilized immunofluorescence to examine DSG2 expression in normal prostate (n = 50) and in a clinically well-characterized cohort of prostate cancer patients (n = 414). Correlation of DSG2 expression with clinico-pathological characteristics and biochemical recurrence was analyzed to assess its clinical significance. Results These studies revealed that DSG2 and DSG4 were specifically expressed in prostatic luminal cells, whereas basal cells lack their expression. In contrast, DSG1 and DSG3 were not expressed in normal prostate epithelium. Further analyses of DSG2 expression in prostate cancer revealed that reduced levels of this biomarker were a significant independent marker of poor clinical outcome. Conclusion Here we report for the first time that a low DSG2 expression phenotype is a useful prognostic biomarker of tumor aggressiveness and may serve as an aid in identifying patients with clinically significant prostate cancer. PMID:24896103

Embryonal Central Nervous System Neoplasms Arising in Infants: A Pediatric Brain Tumor Consortium Study

PubMed Central

McLendon, Roger E.; Adekunle, Adesina; Rajaram, Veena; Kocak, Mehmet; Blaney, Susan M.

2013-01-01

Context Medulloblastomas (MBs) and atypical teratoid/rhabdoid tumors (AT/RTs) can be difficult to distinguish; however, histologic characterization is prognostically important. Objective To determine histologic and phenotypic markers associated with utility progression-free survival (PFS) and overall survival (OS) in children under 3 years of age with MBs and AT/RTs. Design We undertook a histologic and immunophenotypic study of MBs and AT/RTs arising in infants treated on a Pediatric Brain Tumor Consortium study. The 41 girls and 55 boys (aged 2 to 36 months at enrollment) exhibited 42 MBs, 26 AT/RTs and 28 other tumors. Median follow-up was 17.2 months from diagnosis (range: 1.4–93 months). Results Infants with AT/RT exhibited shorter PFS and OS when compared to infants with MBs (P=.0003 and P=.0005, respectively). A lack of nuclear BAF47 immunohistochemical reactivity (IHC) proved reliable in identifying AT/RTs. Among MBs, our data demonstrate that anaplasia correlated with OTX2 reactivity and both OTX2 and moderate to severe anaplasia correlated with PFS but not OS. “Nodularity” may be a positive prognostic factor. Conclusion Distinguishing AT/RT from MBs is clinically important. The diagnoses of AT/RT and MB can be reliably made from H&E stains in the majority of cases. However certain rare small cell variants of AT/RT can be confused with MB. IHC for BAF47 is clinically useful in diagnosing AT/RTs, particularly certain small cell AT/RTs. Among MBs, “nodularity”, absent or mild anaplasia, and lack of OTX2 expression may be important prognostic factors for improved PFS and OS in infants. PMID:21809989

Skeletal involvement in Gaucher disease: An observational multicenter study of prognostic factors in the Argentine Gaucher disease patients.

PubMed

Drelichman, Guillermo; Fernández Escobar, Nicolás; Basack, Nora; Aversa, Luis; Larroude, María Silvia; Aguilar, Gabriela; Szlago, Marina; Schenone, Andrea; Fynn, Alcyra; Cuello, María Fernanda; Aznar, Marcela; Fernández, Ramiro; Ruiz, Alba; Reichel, Paola; Guelbert, Norberto; Robledo, Hugo; Watman, Nora; Bolesina, Moira; Elena, Graciela; Veber, S Ernesto; Pujal, Graciela; Galván, Graciela; Chain, Juan José; Arizo, Adriana; Bietti, Julieta; Bar, Daniel; Dragosky, Marta; Marquez, Marisa; Feldman, Leonardo; Muller, Katja; Zirone, Sandra; Buchovsky, Greogorio; Lanza, Victoria; Sanabria, Alba; Fernández, Ignacio; Jaureguiberry, Rossana; Contte, Marcelo; Barbieri María, Angie; Maro, Alejandra; Zárate, Graciela; Fernández, Gabriel; Rapetti, María Cristina; Donato, Hugo; Degano, Adriana; Kantor, Gustavo; Albina, Roberto; Á Lvarez Bollea, María; Brun, María; Bacciedoni, Viviana; Del Río, Francis; Soberón, Bárbara; Boido, Nazario; Schweri, Maya; Borchichi, Sandra; Welsh, Victoria; Corrales, Marcela; Cedola, Alejandra; Carvani, Analía; Diez, Blanca; Richard, Lucía; Baduel, Ccecilia; Nuñez, Gabriela; Colimodio, Rubén; Barazzutti, Lucía; Medici, Hugo; Meschengieser, Susana; Damiani, Germán; Nucifora, María; Girardi, Beatriz; Gómez, Sergio; Papucci, Maura; Verón, David; Quiroga, Luis; Carro, Gustavo; De Ambrosio, Patricia; Ferro, José; Pujol, Marcelo; Castella, Cristina Cabral; Franco, Liliana; Nisnovich, Gisela; Veloso, María; Pacheco, Isabel; Savarino, Mario; Marino, Andrés; Saavedra, José Luis

2016-10-01

Patients with Gaucher type 1 (GD1) throughout Argentina were enrolled in the Argentine bone project to evaluate bone disease and its determinants. We focused on presence and predictors of bone lesions (BL) and their relationship to therapeutic goals (TG) with timing and dose of enzyme replacement therapy (ERT). A total of 124 patients on ERT were enrolled in a multi-center study. All six TG were achieved by 82% of patients: 70.1% for bone pain and 91.1% for bone crisis. However, despite the fact that bone TGs were achieved, residual bone disease was present in 108 patients on ERT (87%) at time 0. 16% of patients showed new irreversible BL (bone infarcts and avascular osteonecrosis) despite ERT, suggesting that they appeared during ERT or were not detected at the moment of diagnosis. We observed 5 prognostic factors that predicted a higher probability of being free of bone disease: optimal ERT compliance; early diagnosis; timely initiation of therapy; ERT initiation dose ≥45 UI/kg/EOW; and the absence of history of splenectomy. Skeletal involvement was classified into 4 major phenotypic groups according to BL: group 1 (12.9%) without BL; group 2 (28.2%) with reversible BL; group 3 (41.9%) with reversible BL and irreversible chronic BL; and group 4 (16.9%) with acute irreversible BL. Our study identifies prognostic factors for achieving best therapeutic outcomes, introduces new risk stratification for patients and suggests the need for a redefinition of bone TG. Am. J. Hematol. 91:E448-E453, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) Study Design

PubMed Central

Lichtman, Judith H.; Lorenze, Nancy P.; D’Onofrio, Gail; Spertus, John A.; Lindau, Stacy T.; Morgan, Thomas M.; Herrin, Jeph; Bueno, Héctor; Mattera, Jennifer A.; Ridker, Paul M.; Krumholz, Harlan M.

2011-01-01

Background Among individuals with ischemic heart disease, young women with an acute myocardial infarction (AMI) represent an extreme phenotype associated with an excess mortality risk. While women younger than 55 years of age account for less than 5% of hospitalized AMI events, almost 16,000 deaths are reported annually in this group, making heart disease a leading killer of young women. Despite a higher risk of mortality compared with similarly aged men, young women have been the subject of few studies. Methods Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) is a large, observational study of the presentation, treatment and outcomes of young women and men with AMI. VIRGO will enroll 2,000 women, 18–55 years of age, with AMI and a comparison cohort of 1,000 men with AMI from more than 100 participating hospitals. The aims of the study are: to determine sex differences in the distribution and prognostic importance of biological, demographic, clinical, and psychosocial risk factors; determine whether there are sex differences in the quality of care received by young AMI patients; and determine how these factors contribute to sex differences in outcomes (including mortality, hospitalization and health status). Blood serum and DNA for consenting participants will be stored for future studies. Conclusions VIRGO will seek to identify novel and prognostic factors that contribute to outcomes in this young AMI population. Results from the study will be used to develop clinically useful risk-stratification models for young AMI patients, explain sex differences in outcomes and identify targets for intervention. PMID:21081748

Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors

PubMed Central

Sorzano, Carlos O. S.; Pascual-Montano, Alberto; Carazo, Jose M.

2017-01-01

Benign neurofibromas, the main phenotypic manifestations of the rare neurological disorder neurofibromatosis type 1, degenerate to malignant tumors associated to poor prognosis in about 10% of patients. Despite efforts in the field of (epi)genomics, the lack of prognostic biomarkers with which to predict disease evolution frustrates the adoption of appropriate early therapeutic measures. To identify potential biomarkers of malignant neurofibroma transformation, we integrated four human experimental studies and one for mouse, using a gene score-based meta-analysis method, from which we obtained a score-ranked signature of 579 genes. Genes with the highest absolute scores were classified as promising disease biomarkers. By grouping genes with similar neurofibromatosis-related profiles, we derived panels of potential biomarkers. The addition of promoter methylation data to gene profiles indicated a panel of genes probably silenced by hypermethylation. To identify possible therapeutic treatments, we used the gene signature to query drug expression databases. Trichostatin A and other histone deacetylase inhibitors, as well as cantharidin and tamoxifen, were retrieved as putative therapeutic means to reverse the aberrant regulation that drives to malignant cell proliferation and metastasis. This in silico prediction corroborated reported experimental results that suggested the inclusion of these compounds in clinical trials. This experimental validation supported the suitability of the meta-analysis method used to integrate several sources of public genomic information, and the reliability of the gene signature associated to the malignant evolution of neurofibromas to generate working hypotheses for prognostic and drug-responsive biomarkers or therapeutic measures, thus showing the potential of this in silico approach for biomarker discovery. PMID:28542306

Early Prognostication Markers in Cardiac Arrest Patients Treated with Hypothermia

PubMed Central

Karapetkova, Maria; Koenig, Matthew A.; Jia, Xiaofeng

2015-01-01

Background and purpose Established prognostication markers, such as clinical findings, electroencephalography (EEG), and biochemical markers, used by clinicians to predict neurologic outcome after cardiac arrest (CA) are altered under therapeutic hypothermia (TH) conditions and their validity remains uncertain. Methods MEDLINE and EMBASE were searched for evidence on the current standards for neurologic outcome prediction for out-of-hospital CA patients treated with TH and the validity of a wide range of prognostication markers. Relevant studies that suggested one or several established biomarkers, and multimodal approaches for prognostication were included and reviewed. Results While the prognostic accuracy of various tests has been questioned after TH, pupillary light reflexes and somatosensory evoked potentials (SSEP) are still strongly associated with negative outcome for early prognostication. Increasingly, EEG background activity has also been identified as a valid predictor for outcome after 72 hours after CA and a preferred prognostic method in clinical settings. Neuroimaging techniques, such as MRI and CT, can identify functional and structural brain injury, but are not readily available at the patient’s bedside because of limited availability and high costs. Conclusions A multimodal algorithm composed of neurological examination, EEG-based quantitative testing, and SSEP, in conjunction with newer MRI sequences, if available, holds promise for accurate prognostication in CA patients treated with TH. In order to avoid premature withdrawal of care, prognostication should be performed later than 72 hours after CA. PMID:26228521

Early prognostication markers in cardiac arrest patients treated with hypothermia.

PubMed

Karapetkova, M; Koenig, M A; Jia, X

2016-03-01

Established prognostication markers, such as clinical findings, electroencephalography (EEG) and biochemical markers, used by clinicians to predict neurological outcome after cardiac arrest (CA) are altered under therapeutic hypothermia (TH) conditions and their validity remains uncertain. MEDLINE and Embase were searched for evidence on the current standards for neurological outcome prediction for out-of-hospital CA patients treated with TH and the validity of a wide range of prognostication markers. Relevant studies that suggested one or several established biomarkers and multimodal approaches for prognostication are included and reviewed. Whilst the prognostic accuracy of various tests after TH has been questioned, pupillary light reflexes and somatosensory evoked potentials are still strongly associated with negative outcome for early prognostication. Increasingly, EEG background activity has also been identified as a valid predictor for outcome after 72 h after CA and a preferred prognostic method in clinical settings. Neuroimaging techniques, such as magnetic resonance imaging and computed tomography, can identify functional and structural brain injury but are not readily available at the patient's bedside because of limited availability and high costs. A multimodal algorithm composed of neurological examination, EEG-based quantitative testing and somatosensory evoked potentials, in conjunction with newer magnetic resonance imaging sequences, if available, holds promise for accurate prognostication in CA patients treated with TH. In order to avoid premature withdrawal of care, prognostication should be performed more than 72 h after CA. © 2015 EAN.

An internally validated new clinical and inflammation-based prognostic score for patients with advanced hepatocellular carcinoma treated with sorafenib.

PubMed

Diaz-Beveridge, R; Bruixola, G; Lorente, D; Caballero, J; Rodrigo, E; Segura, Á; Akhoundova, D; Giménez, A; Aparicio, J

2018-03-01

Sorafenib is a standard treatment for patients (pts) with advanced hepatocellular carcinoma (aHCC), although the clinical benefit is heterogeneous between different pts groups. Among novel prognostic factors, a low baseline neutrophil-to-lymphocyte ratio (bNLR) and early-onset diarrhoea have been linked with a better prognosis. To identify prognostic factors in pts with aHCC treated with 1st-line sorafenib and to develop a new prognostic score to guide management. Retrospective review of 145 pts bNLR, overall toxicity, early toxicity rates and overall survival (OS) were assessed. Univariate and multivariate analysis of prognostic factors for OS was performed. The prognostic score was calculated from the coefficients found in the Cox analysis. ROC curves and pseudoR2 index were used for internal validation. Discrimination ability and calibration were tested by Harrel's c-index (HCI) and Akaike criteria (AIC). The optimal bNLR cut-off for the prediction of OS was 4 (AUC 0.62). Independent prognostic factors in multivariate analysis for OS were performance status (PS) (p < .0001), Child-Pugh (C-P) score (p = 0.005), early-onset diarrhoea (p = 0.006) and BNLR (0.011). The prognostic score based on these four variables was found efficient (HCI = 0.659; AIC = 1.180). Four risk groups for OS could be identified: a very low-risk (median OS = 48.6 months), a low-risk (median OS = 11.6 months), an intermediate-risk (median OS = 8.3 months) and a high-risk group (median OS = 4.4 months). PS and C-P score were the main prognostic factors for OS, followed by early-onset diarrhoea and bNLR. We identified four risk groups for OS depending on these parameters. This prognostic model could be useful for patient stratification, but an external validation is needed.

Prognostic indicators of 6-month mortality in elderly people with advanced dementia: A systematic review

PubMed Central

Brown, Meghan A; Sampson, Elizabeth L; Jones, Louise

2013-01-01

Background: For end-of-life dementia patients, palliative care offers a better quality of life than continued aggressive or burdensome medical interventions. To provide the best care options to dementia sufferers, validated, reliable, sensitive, and accurate prognostic tools to identify end-of-life dementia stages are necessary. Aim: To identify accurate prognosticators of mortality in elderly advanced dementia patients consistently reported in the literature. Design: Systematic literature review. Data sources: PubMed, Embase, and PsycINFO databases were searched up to September 2012. Reference lists of included studies were also searched. Inclusion criteria were studies measuring factors specifically related to 6-month outcome in patients diagnosed with dementia in any residential or health-care setting. Results: Seven studies met the inclusion criteria, five of which were set in the United States and two in Israel. Methodology and prognostic outcomes varied greatly between the studies. All but one study found that Functional Assessment Staging phase 7c, currently widely used to assess hospice admission eligibility in the United States, was not a reliable predictor of 6-month mortality. The most common prognostic variables identified related to nutrition/nourishment, or eating habits, followed by increased risk on dementia severity scales and comorbidities. Conclusions: Although the majority of studies agreed that the Functional Assessment Staging 7c criterion was not a reliable predictor of 6-month mortality, we found a lack of prognosticator concordance across the literature. Further studies are essential to identify reliable, sensitive, and specific prognosticators, which can be applied to the clinical setting and allow increased availability of palliative care to dementia patients. PMID:23175514

A primary tumor of mixed histological type is a novel poor prognostic factor for patients undergoing resection of liver metastasis from gastric cancer.

PubMed

Ikari, Naoki; Taniguchi, Kiyoaki; Serizawa, Akiko; Yamada, Takuji; Yamamoto, Masakazu; Furukawa, Toru

2017-05-01

Surgical resection can be an option for the treatment of metastatic liver tumors originating from gastric cancer; however, its prognostic impact is controversial. The aim of this study was to identify prognostic factors in patients with surgical resection of liver metastasis from gastric cancer. We retrospectively analyzed the clinicopathological features of 38 consecutive patients undergoing hepatectomy for metastatic tumors from gastric cancer in our institution between 1990 and 2014. The median overall survival of the patients was 28 months. The 5-year survival rate was 33.9%. Primary tumors of a mixed histological type, and residual tumors during the course of treatment were identified as significant independent poor prognostic factors. Histological evaluation of primary tumors may aid to identify patients suitable for undergoing surgical resection of liver metastasis from gastric cancer. © 2017 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

A prognostic mutation panel for predicting cancer recurrence in stages II and III colorectal cancer.

PubMed

Sho, Shonan; Court, Colin M; Winograd, Paul; Russell, Marcia M; Tomlinson, James S

2017-12-01

Approximately 20-40% of stage II/III colorectal cancer (CRC) patients develop relapse. Clinicopathological factors alone are limited in detecting these patients, resulting in potential under/over-treatment. We sought to identify a prognostic tumor mutational profile that could predict CRC recurrence. Whole-exome sequencing data were obtained for 207 patients with stage II/III CRC from The Cancer Genome Atlas. Mutational landscape in relapse-free versus relapsed cohort was compared using Fisher's exact test, followed by multivariate Cox regression to identify genes associated with cancer recurrence. Bootstrap-validation was used to examine internal/external validity. We identified five prognostic genes (APAF1, DIAPH2, NTNG1, USP7, and VAV2), which were combined to form a prognostic mutation panel. Patients with ≥1 mutation(s) within this five-gene panel had worse prognosis (3-yr relapse-free survival [RFS]: 53.0%), compared to patients with no mutation (3-yr RFS: 84.3%). In multivariate analysis, the five-gene panel remained prognostic for cancer recurrence independent of stage and high-risk features (hazard ratio 3.63, 95%CI [1.93-6.83], P < 0.0001). Furthermore, its prognostic accuracy was superior to the American Joint Commission on Cancer classification (concordance-index: 0.70 vs 0.54). Our proposed mutation panel identifies CRC patients at high-risk for recurrence, which may help guide adjuvant therapy and post-operative surveillance protocols. © 2017 Wiley Periodicals, Inc.

Prediction of the First Variceal Haemorrhage

PubMed Central

1997-01-01

We followed 87 cirrhotic patients with esophageal varices and without previous hemorrhage for a mean period of 24 mo to prospectively evaluate the occurance of variceal bleeding within (early) or after (late) 6 mo from entry and the contribution of portal Doppler ultrasound parameters to the prediction of early and late hemorrhage. Clinical, biochemical, endoscopic and portal Doppler ultrasound parameters were recorded at entry. Variceal bleeding occurred in 22 patients (25.3%). Nine (40.9%) bled within the first 6 mo. Cox regression analysis identified variceal size, cherry-red spots, serum bilirubin and congestion index of the portal vein (the ratio of portal vein [cross-sectional area] and portal blood flow velocity) as the only independent predictors of first variceal hemorrhage. Discriminant analysis was used to find the prognostic index cut off points to identify patients who bled within 6 mo (prognostic group 1) or after 6 mo (prognostic group 2) or remained free of bleeding (prognostic group 3). The cumulative proportion of patients correctly classified was 73% in prognostic group 1, 47% in prognostic group 2 and more than 80% in prognostic group 3. The addition of Doppler ultrasound flowmetry to clinical, biochemical and endoscopic parameter only improved the classification of patients with early bleeding. PMID:9184882

Assessment of Total Lesion Glycolysis by 18F FDG PET/CT Significantly Improves Prognostic Value of GEP and ISS in Myeloma.

PubMed

McDonald, James E; Kessler, Marcus M; Gardner, Michael W; Buros, Amy F; Ntambi, James A; Waheed, Sarah; van Rhee, Frits; Zangari, Maurizio; Heuck, Christoph J; Petty, Nathan; Schinke, Carolina; Thanendrarajan, Sharmilan; Mitchell, Alan; Hoering, Antje; Barlogie, Bart; Morgan, Gareth J; Davies, Faith E

2017-04-15

Purpose: Fluorine-18 fluorodeoxyglucose positron emission tomography with CT attenuation correction ( 18 F-FDG PET/CT) is useful in the detection and enumeration of focal lesions and in semiquantitative characterization of metabolic activity (glycolytic phenotype) by calculation of glucose uptake. Total lesion glycolysis (TLG) and metabolic tumor volume (MTV) have the potential to improve the value of this approach and enhance the prognostic value of disease burden measures. This study aims to determine whether TLG and MTV are associated with progression-free survival (PFS) and overall survival (OS), and whether they improve risk assessments such as International Staging System (ISS) stage and GEP70 risk. Experimental Design: 192 patients underwent whole body PET/CT in the Total Therapy 3A (TT3A) trial and were evaluated using three-dimensional region-of-interest analysis with TLG, MTV, and standard measurement parameters derived for all focal lesions with peak SUV above the background red marrow signal. Results: In multivariate analysis, baseline TLG > 620 g and MTV > 210 cm 3 remained a significant factor of poor PFS and OS after adjusting for baseline myeloma variables. Combined with the GEP70 risk score, TLG > 205 g identifies a high-risk-behaving subgroup with poor expected survival. In addition, TLG > 205 g accurately divides ISS stage II patients into two subgroups with similar outcomes to ISS stage I and ISS stage III, respectively. Conclusions: TLG and MTV have significant survival implications at baseline and offer a more precise quantitation of the glycolytic phenotype of active disease. These measures can be assessed more readily than before using FDA-approved software and should be standardized and incorporated into clinical trials moving forward. Clin Cancer Res; 23(8); 1981-7. ©2016 AACR . ©2016 American Association for Cancer Research.

Prognosis of Pain and Physical Functioning in Patients With Knee Osteoarthritis: A Systematic Review and Meta-Analysis.

PubMed

de Rooij, Mariëtte; van der Leeden, Marike; Heymans, Martijn W; Holla, Jasmijn F M; Häkkinen, Arja; Lems, Willem F; Roorda, Leo D; Veenhof, Cindy; Sanchez-Ramirez, Diana C; de Vet, Henrica C W; Dekker, Joost

2016-04-01

To systematically summarize the literature on the course of pain in patients with knee osteoarthritis (OA), prognostic factors that predict deterioration of pain, the course of physical functioning, and prognostic factors that predict deterioration of physical functioning in persons with knee OA. A search was conducted in PubMed, CINAHL, Embase, Psych-INFO, and SPORTDiscus up to January 2014. A meta-analysis and a qualitative data synthesis were performed. Of the 58 studies included, 39 were of high quality. High heterogeneity across studies (I(2)  >90%) and within study populations (reflected by large SDs of change scores) was found. Therefore, the course of pain and physical functioning was interpreted to be indistinct. We found strong evidence for a number of prognostic factors predicting deterioration in pain (e.g., higher knee pain at baseline, bilateral knee symptoms, and depressive symptoms). We also found strong evidence for a number of prognostic factors predicting deterioration in physical functioning (e.g., worsening in radiographic OA, worsening of knee pain, lower knee extension muscle strength, lower walking speed, and higher comorbidity count). Because of high heterogeneity across studies and within study populations, no conclusions can be drawn with regard to the course of pain and physical functioning. These findings support current research efforts to define subgroups or phenotypes within knee OA populations. Strong evidence was found for knee characteristics, clinical factors, and psychosocial factors as prognostics of deterioration of pain and physical functioning. © 2016, American College of Rheumatology.

Evaluating biomarkers for prognostic enrichment of clinical trials.

PubMed

Kerr, Kathleen F; Roth, Jeremy; Zhu, Kehao; Thiessen-Philbrook, Heather; Meisner, Allison; Wilson, Francis Perry; Coca, Steven; Parikh, Chirag R

2017-12-01

A potential use of biomarkers is to assist in prognostic enrichment of clinical trials, where only patients at relatively higher risk for an outcome of interest are eligible for the trial. We investigated methods for evaluating biomarkers for prognostic enrichment. We identified five key considerations when considering a biomarker and a screening threshold for prognostic enrichment: (1) clinical trial sample size, (2) calendar time to enroll the trial, (3) total patient screening costs and the total per-patient trial costs, (4) generalizability of trial results, and (5) ethical evaluation of trial eligibility criteria. Items (1)-(3) are amenable to quantitative analysis. We developed the Biomarker Prognostic Enrichment Tool for evaluating biomarkers for prognostic enrichment at varying levels of screening stringency. We demonstrate that both modestly prognostic and strongly prognostic biomarkers can improve trial metrics using Biomarker Prognostic Enrichment Tool. Biomarker Prognostic Enrichment Tool is available as a webtool at http://prognosticenrichment.com and as a package for the R statistical computing platform. In some clinical settings, even biomarkers with modest prognostic performance can be useful for prognostic enrichment. In addition to the quantitative analysis provided by Biomarker Prognostic Enrichment Tool, investigators must consider the generalizability of trial results and evaluate the ethics of trial eligibility criteria.

State of the art and taxonomy of prognostics approaches, trends of prognostics applications and open issues towards maturity at different technology readiness levels

NASA Astrophysics Data System (ADS)

Javed, Kamran; Gouriveau, Rafael; Zerhouni, Noureddine

2017-09-01

Integrating prognostics to a real application requires a certain maturity level and for this reason there is a lack of success stories about development of a complete Prognostics and Health Management system. In fact, the maturity of prognostics is closely linked to data and domain specific entities like modeling. Basically, prognostics task aims at predicting the degradation of engineering assets. However, practically it is not possible to precisely predict the impending failure, which requires a thorough understanding to encounter different sources of uncertainty that affect prognostics. Therefore, different aspects crucial to the prognostics framework, i.e., from monitoring data to remaining useful life of equipment need to be addressed. To this aim, the paper contributes to state of the art and taxonomy of prognostics approaches and their application perspectives. In addition, factors for prognostics approach selection are identified, and new case studies from component-system level are discussed. Moreover, open challenges toward maturity of the prognostics under uncertainty are highlighted and scheme for an efficient prognostics approach is presented. Finally, the existing challenges for verification and validation of prognostics at different technology readiness levels are discussed with respect to open challenges.

Hilar fat infiltration: A new prognostic factor in metastatic clear cell renal cell carcinoma with first-line sunitinib treatment.

PubMed

Kammerer-Jacquet, Solène-Florence; Brunot, Angelique; Bensalah, Karim; Campillo-Gimenez, Boris; Lefort, Mathilde; Bayat, Sahar; Ravaud, Alain; Dupuis, Frantz; Yacoub, Mokrane; Verhoest, Gregory; Peyronnet, Benoit; Mathieu, Romain; Lespagnol, Alexandra; Mosser, Jean; Edeline, Julien; Laguerre, Brigitte; Bernhard, Jean-Christophe; Rioux-Leclercq, Nathalie

2017-10-01

The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib. In a multicentric study, we retrospectively included 90 patients and studied the corresponding ccRCC at the pathological, immunohistochemical, and molecular levels. Patient and tumor characteristics were compared using univariate and multivariate analysis. All the features were then studied by Cox models for prognostic effect. HFI was found in 42 patients (46.7%), who had worse prognosis (Heng criteria) (P = 0.003), liver metastases (P = 0.036), and progressive diseases at first radiological evaluation (P = 0.024). The corresponding ccRCC was associated with poor pathological prognostic factors that are well known in nonmetastatic ccRCC. For these patients, median progression-free survival was 4 months vs. 13 months (P = 0.02), and median overall survival was 14 months vs. 29 months (P = 0.006). In a multivariate Cox model integrating all the variables, only poor prognosis, according to the Heng criteria and HFI, remained independently associated with both progression-free survival and overall survival. HFI was demonstrated for the first time to be an independent poor prognostic factor. Its potential role in predicting resistance to antiangiogenic therapy warrants further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

Preoperative prognostic factors for mortality in peptic ulcer perforation: a systematic review.

PubMed

Møller, Morten Hylander; Adamsen, Sven; Thomsen, Reimar Wernich; Møller, Ann Merete

2010-08-01

Mortality and morbidity following perforated peptic ulcer (PPU) is substantial and probably related to the development of sepsis. During the last three decades a large number of preoperative prognostic factors in patients with PPU have been examined. The aim of this systematic review was to summarize available evidence on these prognostic factors. MEDLINE (January 1966 to June 2009), EMBASE (January 1980 to June 2009), and the Cochrane Library (Issue 3, 2009) were screened for studies reporting preoperative prognostic factors for mortality in patients with PPU. The methodological quality of the included studies was assessed. Summary relative risks with 95% confidence intervals for the identified prognostic factors were calculated and presented as Forest plots. Fifty prognostic studies with 37 prognostic factors comprising a total of 29,782 patients were included in the review. The overall methodological quality was acceptable, yet only two-thirds of the studies provided confounder adjusted estimates. The studies provided strong evidence for an association of older age, comorbidity, and use of NSAIDs or steroids with mortality. Shock upon admission, preoperative metabolic acidosis, tachycardia, acute renal failure, low serum albumin level, high American Society of Anaesthesiologists score, and preoperative delay >24 h were associated with poor prognosis. In patients with PPU, a number of negative prognostic factors can be identified prior to surgery, and many of these seem to be related to presence of the sepsis syndrome.

Cancer predisposition syndromes: lessons for truly precision medicine.

PubMed

Glaire, Mark A; Brown, Matthew; Church, David N; Tomlinson, Ian

2017-01-01

Cancer predisposition syndromes are typically uncommon, monogenic, high-penetrance disorders. Despite their rarity, they have proven to be highly clinically relevant in directing cancer prevention strategies. As such, they share notable similarities with an expanding class of low-frequency somatic mutations that are associated with a striking prognostic or predictive effect in the tumours in which they occur. In this review, we highlight these commonalities, with particular reference to mutations in the proofreading domain of replicative DNA polymerases. These molecular phenotypes may occur as either germline or somatic events, and in the latter case, have been shown to confer a favourable prognosis and potential increased benefit from immune checkpoint inhibition. We note that incorporation of these variants into clinical management algorithms will help refine patient management, and that this will be further improved by the inclusion of other germline variants, such as those that determine the likelihood of benefit or toxicity from anti-neoplastic therapy. Finally, we propose that such integrated patient and tumour profiling will be essential if we are to deliver truly precision medicine for cancer patients, but in a similar way to rare germline mutations, we must ensure that we identify and utilize rare somatic mutations with strong predictive and prognostic effects. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Molecular biomarkers for progression of intraductal papillary mucinous neoplasm of the pancreas.

PubMed

Kuboki, Yuko; Shimizu, Kyoko; Hatori, Takashi; Yamamoto, Masakazu; Shibata, Noriyuki; Shiratori, Keiko; Furukawa, Toru

2015-03-01

We aimed to identify molecular biomarkers for assessing the progression of intraductal papillary mucinous neoplasm of the pancreas (IPMN). We retrospectively investigated molecular aberrations and their associations with clinicopathological features in 172 IPMNs. GNAS and KRAS mutations were detected in 48% and 56% of IPMNs, respectively. No mutations of EGFR, PIK3CA GNAO1, GNAQ, or GNAI2 were observed. Significant associations were observed between IPMN morphological types and GNAS mutations, KRAS mutations, the expression of phosphorylated MAPK (pMAPK), AKT, and phosphorylated AKT (pAKT), nuclear accumulation of β-catenin, SMAD4 loss, and TP53 overexpression; histological grades and the expression of EGFR, pMAPK, AKT, and pAKT, the nuclear β-catenin, SMAD4 loss, and TP53 overexpression; invasive phenotypes and KRAS mutations, the nuclear β-catenin, and SMAD4 loss; and prognosis and SMAD4 loss and TP53 overexpression. Multivariate analysis to compare prognostic impacts of multiple molecular features revealed that TP53 overexpression was an independent prognostic factor (P = 0.030; hazard ratio, 5.533). These results indicate that mutations in GNAS and KRAS, the expression of EGFR and pMAPK, the nuclear β-catenin, SMAD4 loss, and TP53 overexpression may be relevant for assessing the clinical course of IPMN, including its progression into different morphological types, invasion, and prognosis.

Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Upregulation of antioxidant genes correlates with regression of melanoma malignancy and with malignant progression when downregulated

PubMed Central

Berenstein, Ariel; Notcovich, Cintia; Cerda, María B.; Klamt, Fabio; Chernomoretz, Ariel; Durán, Hebe

2016-01-01

Reactive oxygen species (ROS) are implicated in tumor transformation. The antioxidant system (AOS) protects cells from ROS damage. However, it is also hijacked by cancers cells to proliferate within the tumor. Thus, identifying proteins altered by redox imbalance in cancer cells is an attractive prognostic and therapeutic tool. Gene expression microarrays in A375 melanoma cells with different ROS levels after overexpressing catalase were performed. Dissimilar phenotypes by differential compensation to hydrogen peroxide scavenging were generated. The melanotic A375-A7 (A7) upregulated TYRP1, CNTN1 and UCHL1 promoting melanogenesis. The metastatic A375-G10 (G10) downregulated MTSS1 and TIAM1, proteins absent in metastasis. Moreover, differential coexpression of AOS genes (EPHX2, GSTM3, MGST1, MSRA, TXNRD3, MGST3 and GSR) was found in A7 and G10. Their increase in A7 improved its AOS ability and therefore, oxidative stress response, resembling less aggressive tumor cells. Meanwhile, their decrease in G10 revealed a disruption in the AOS and therefore, enhanced its metastatic capacity. These gene signatures, not only bring new insights into the physiopathology of melanoma, but also could be relevant in clinical prognostic to classify between non aggressive and metastatic melanomas. PMID:27206673

Prognostic factors in patients with spinal metastasis: a systematic review and meta-analysis.

PubMed

Luksanapruksa, Panya; Buchowski, Jacob M; Hotchkiss, William; Tongsai, Sasima; Wilartratsami, Sirichai; Chotivichit, Areesak

2017-05-01

Incidence of symptomatic spinal metastasis has increased owing to improvement in treatment of the disease. One of the key factors that influences decision-making is expected patient survival. To our knowledge, no systematic reviews or meta-analysis have been conducted that review independent prognostic factors in spinal metastases. This study aimed to determine independent prognostic factors that affect outcome in patients with metastatic spine disease. This is a systematic literature review and meta-analysis of publications for prognostic factors in spinal metastatic disease. Pooled patient results from cohort and observational studies. Meta-analysis for poor prognostic factors as determined by hazard ratio (HR) and 95% confidential interval (95% CI). We systematically searched relevant publications in PubMed and Embase. The following search terms were used: ("'spinal metastases'" OR "'vertebral metastases'" OR "spinal metastasis" OR 'vertebral metastases') AND ('"prognostic factors"' OR "'survival'"). Inclusion criteria were prospective and retrospective cohort series that report HR and 95% CI of independent prognostic factors from multivariate analysis. Two reviewers independently assessed all papers. The quality of included papers was assessed by using Newcastle-Ottawa Scale for cohort studies and publication bias was assessed by using funnel plot, Begg test, and Egger test. The prognostic factors that were mentioned in at least three publications were pooled. Meta-analysis was performed using HR and 95% CI as the primary outcomes of interest. Heterogeneity was assessed using the I 2 method. A total of 3,959 abstracts (1,382 from PubMed and 2,577 from Embase) were identified through database search and 40 publications were identified through review of cited publications. The reviewers selected a total of 51 studies for qualitative synthesis and 43 studies for meta-analysis. Seventeen poor prognostic factors were identified. These included presence of a neurologic deficit before surgery, non-ambulatory status before radiotherapy (RT), non-ambulatory status before surgery, presence of bone metastases, presence of multiple bone metastases (>2 sites), presence of multiple spinal metastases (>3 sites), development of motor deficit in <7 days before initiating RT, development of motor deficit in <14 days before initiating RT, time interval from cancer diagnosis to RT <15 months, Karnofsky Performance Score (KPS) 10-40, KPS 50-70, KPS<70, Eastern Cooperative Oncology Group (ECOG) grade 3-4, male gender, presence of visceral metastases, moderate growth tumor on Tomita score (TS) classification, and rapid growth tumor on TS classification. Seventeen independent poor prognostic factors were identified in this study. These can be categorized into cancer-specific and nonspecific prognostic factors. A tumor-based prognostic scoring system that combines all specific and general factors may enhance the accuracy of survival prediction in patients with metastatic spine disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Nevus count associations with pigmentary phenotype, histopathological melanoma characteristics and survival from melanoma

PubMed Central

Taylor, Nicholas J.; Thomas, Nancy E.; Anton-Culver, Hoda; Armstrong, Bruce K.; Begg, Colin B.; Busam, Klaus J.; Cust, Anne E.; Dwyer, Terence; From, Lynn; Gallagher, Richard P.; Gruber, Stephen B.; Nishri, Diane E.; Orlow, Irene; Rosso, Stefano; Venn, Alison J.; Zanetti, Roberto; Berwick, Marianne; Kanetsky, Peter A.

2016-01-01

Although nevus count is an established risk factor for melanoma, relationships between nevus number and patient and tumor characteristics have not been well studied and the influence of nevus count on melanoma-specific survival is equivocal. Using data from the Genes, Environment, and Melanoma (GEM) study, a large population-based study of primary cutaneous melanoma, we evaluated associations between number of nevi and patient features, including sun-sensitivity summarized in a phenotypic index, and tumor characteristics, and we assessed the association of nevus count with melanoma-specific survival. Higher nevus counts were independently and positively associated with male gender and younger age at diagnosis and inversely associated with lentigo maligna histology. We observed a borderline significant trend of poorer melanoma-specific survival with increasing quartile of nevus count, but little or no association between number of nevi and pigmentary phenotypic characteristics or prognostic tumor features. PMID:27101944

CpG island methylator phenotype is an independent predictor of survival after curative resection for colorectal cancer: A prospective cohort study.

PubMed

Kim, Chang Hyun; Huh, Jung Wook; Kim, Hyeong Rok; Kim, Young Jin

2017-08-01

The CpG island methylator phenotype (CIMP) is found in approximately 30% of colorectal cancer (CRC) cases. However, the role of CIMP status in predicting oncologic outcomes in curatively resected CRC is still unclear. Between January 2006 and December 2006, we retrospectively reviewed 157 consecutive patients who underwent curative surgery for CRC. Prognostic significance of CIMP status was evaluated using reverse transcriptase-polymerase chain reaction. CIMP-high (H) and CIMP-none/low (N/L) tumors were found in 50 cases (31.8%) and 107 cases (68.2%), respectively. CIMP-H tumors were significantly associated with female sex, colonic location, poorly/mucinous histologic type, higher T category, perineural invasion, and MSI-high status (P = 0.001). During a median of 64.5 months, tumor recurrence developed in 47 (29.9%) patients. The 5-year disease-free survival for CIMP-H and CIMP-N/L was 61.4% and 76.3% (P = 0.018). In addition, multivariate analysis showed that CIMP-H was also a significant prognostic factor (P = 0.042). When analysis was performed according to anatomical location, more marked survival differences were observed in patients with colon cancer (P = 0.026) than in patients with rectal cancer (P = 0.210). Similarly, the role of CIMP status as a prognostic indicator was more prominent in patients with stage I/II (P = 0.006) than in patients with stage III/IV CRC (P = 0.65). DNA methylation status can be considered as a useful predictor of survival after CRC surgery, particularly for patients with stage I/II disease or colon cancer. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

A novel gene expression-based prognostic scoring system to predict survival in gastric cancer

DOE PAGES

Wang, Pin; Wang, Yunshan; Hang, Bo; ...

2016-07-11

Analysis of gene expression patterns in gastric cancer (GC) can help to identify a comprehensive panel of gene biomarkers for predicting clinical outcomes and to discover potential new therapeutic targets. Here, a multi-step bioinformatics analytic approach was developed to establish a novel prognostic scoring system for GC. We first identified 276 genes that were robustly differentially expressed between normal and GC tissues, of which, 249 were found to be significantly associated with overall survival (OS) by univariate Cox regression analysis. The biological functions of 249 genes are related to cell cycle, RNA/ncRNA process, acetylation and extracellular matrix organization. A networkmore » was generated for view of the gene expression architecture of 249 genes in 265 GCs. Finally, we applied a canonical discriminant analysis approach to identify a 53-gene signature and a prognostic scoring system was established based on a canonical discriminant function of 53 genes. The prognostic scores strongly predicted patients with GC to have either a poor or good OS. Our study raises the prospect that the practicality of GC patient prognosis can be assessed by this prognostic scoring system.« less

A novel gene expression-based prognostic scoring system to predict survival in gastric cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Pin; Wang, Yunshan; Hang, Bo

Analysis of gene expression patterns in gastric cancer (GC) can help to identify a comprehensive panel of gene biomarkers for predicting clinical outcomes and to discover potential new therapeutic targets. Here, a multi-step bioinformatics analytic approach was developed to establish a novel prognostic scoring system for GC. We first identified 276 genes that were robustly differentially expressed between normal and GC tissues, of which, 249 were found to be significantly associated with overall survival (OS) by univariate Cox regression analysis. The biological functions of 249 genes are related to cell cycle, RNA/ncRNA process, acetylation and extracellular matrix organization. A networkmore » was generated for view of the gene expression architecture of 249 genes in 265 GCs. Finally, we applied a canonical discriminant analysis approach to identify a 53-gene signature and a prognostic scoring system was established based on a canonical discriminant function of 53 genes. The prognostic scores strongly predicted patients with GC to have either a poor or good OS. Our study raises the prospect that the practicality of GC patient prognosis can be assessed by this prognostic scoring system.« less

Identification of immunophenotypic subtypes with different prognoses in extranodal natural killer/T-cell lymphoma, nasal type.

PubMed

Yu, Jian-Bo; Zuo, Zhuo; Zhang, Wen-Yan; Yang, Qun-Pei; Zhang, Ying-Chun; Tang, Yuan; Zhao, Sha; Mo, Xian-Ming; Liu, Wei-Ping

2014-11-01

To analyze the differentiation characteristics of extranodal natural killer/T-cell lymphoma, nasal type, one nude mouse model, cell lines SNK6 and SNT8, and 16 fresh human samples were analyzed by flow cytometry immunophenotyping and immunohistochemistry staining; and 115 archived cases were used for phenotypic detection and prognostic analysis. We found that CD25 was expressed by most tumor cells in all samples, and CD56(+)CD25(+) cells were the predominant population in the mouse model, the 2 cell lines, and 10 of the 16 fresh tumor samples; in the other 6 fresh tumor samples, the predominant cell population was of the CD16(+)CD25(+) phenotype, and only a minor population showed the CD56(+)CD25(+) phenotype. The phenotype detected by immunohistochemistry staining generally was consistent with the phenotype found by flow cytometry immunophenotyping. According to the expression of CD56 and CD16, 115 cases could be classified into 3 phenotypic subtypes: CD56(-)CD16(-), CD56(+)CD16(-), and CD56(dim/-)CD16(+). Patients with tumors of the CD56(dim/-)CD16(+) phenotype had a poorer prognosis than patients with tumors of the other phenotypes. Differentiation of extranodal natural killer/T-cell lymphoma, nasal type apparently resembles the normal natural killer cell developmental pattern, and these tumors can be classified into 3 phenotypic subtypes of different aggressiveness. Expression of CD56(dim/-)CD16(+) implies a poorer prognosis. Copyright © 2014 Elsevier Inc. All rights reserved.

Novel therapeutic strategies in myelodysplastic syndromes: do molecular genetics help?

PubMed

Chung, Stephen S

2016-03-01

Many studies over the past decade have together identified genes that are recurrently mutated in the myelodysplastic syndromes (MDS). We will summarize how this information has informed our understanding of disease pathogenesis and behavior, with an emphasis on how this information may inform therapeutic strategies. Genomic sequencing techniques have allowed for the identification of many recurrently mutated genes in MDS, with the most common mutations being found in epigenetic modifiers and components of the splicing machinery. Although many mutations are associated with clinical outcomes and disease phenotypes, at the current time they add relatively little to already robust clinical prognostic algorithms. However, as molecular genetic data are accumulated in larger numbers of patients, it is likely that the clinical significance of co-occurring mutations and less common mutations will come to light. Finally, mutated genes may identify biologically distinct subgroups of MDS that may benefit from novel therapies, and a subset of these genes may themselves serve as therapeutic targets. Advances in our knowledge of the molecular genetics of MDS have significantly improved our understanding of disease biology and promise to improve tools for clinical decision-making and identify new therapies for patients.

Metabolomics and Personalized Medicine.

PubMed

Koen, Nadia; Du Preez, Ilse; Loots, Du Toit

2016-01-01

Current clinical practice strongly relies on the prognosis, diagnosis, and treatment of diseases using methods determined and averaged for the specific diseased cohort/population. Although this approach complies positively with most patients, misdiagnosis, treatment failure, relapse, and adverse drug effects are common occurrences in many individuals, which subsequently hamper the control and eradication of a number of diseases. These incidences can be explained by individual variation in the genome, transcriptome, proteome, and metabolome of a patient. Various "omics" approaches have investigated the influence of these factors on a molecular level, with the intention of developing personalized approaches to disease diagnosis and treatment. Metabolomics, the newest addition to the "omics" domain and the closest to the observed phenotype, reflects changes occurring at all molecular levels, as well as influences resulting from other internal and external factors. By comparing the metabolite profiles of two or more disease phenotypes, metabolomics can be applied to identify biomarkers related to the perturbation being investigated. These biomarkers can, in turn, be used to develop personalized prognostic, diagnostic, and treatment approaches, and can also be applied to the monitoring of disease progression, treatment efficacy, predisposition to drug-related side effects, and potential relapse. In this review, we discuss the contributions that metabolomics has made, and can potentially still make, towards the field of personalized medicine. © 2016 Elsevier Inc. All rights reserved.

Machine Learning methods for Quantitative Radiomic Biomarkers.

PubMed

Parmar, Chintan; Grossmann, Patrick; Bussink, Johan; Lambin, Philippe; Aerts, Hugo J W L

2015-08-17

Radiomics extracts and mines large number of medical imaging features quantifying tumor phenotypic characteristics. Highly accurate and reliable machine-learning approaches can drive the success of radiomic applications in clinical care. In this radiomic study, fourteen feature selection methods and twelve classification methods were examined in terms of their performance and stability for predicting overall survival. A total of 440 radiomic features were extracted from pre-treatment computed tomography (CT) images of 464 lung cancer patients. To ensure the unbiased evaluation of different machine-learning methods, publicly available implementations along with reported parameter configurations were used. Furthermore, we used two independent radiomic cohorts for training (n = 310 patients) and validation (n = 154 patients). We identified that Wilcoxon test based feature selection method WLCX (stability = 0.84 ± 0.05, AUC = 0.65 ± 0.02) and a classification method random forest RF (RSD = 3.52%, AUC = 0.66 ± 0.03) had highest prognostic performance with high stability against data perturbation. Our variability analysis indicated that the choice of classification method is the most dominant source of performance variation (34.21% of total variance). Identification of optimal machine-learning methods for radiomic applications is a crucial step towards stable and clinically relevant radiomic biomarkers, providing a non-invasive way of quantifying and monitoring tumor-phenotypic characteristics in clinical practice.

Quantitative Stratification of Diffuse Parenchymal Lung Diseases

PubMed Central

Raghunath, Sushravya; Rajagopalan, Srinivasan; Karwoski, Ronald A.; Maldonado, Fabien; Peikert, Tobias; Moua, Teng; Ryu, Jay H.; Bartholmai, Brian J.; Robb, Richard A.

2014-01-01

Diffuse parenchymal lung diseases (DPLDs) are characterized by widespread pathological changes within the pulmonary tissue that impair the elasticity and gas exchange properties of the lungs. Clinical-radiological diagnosis of these diseases remains challenging and their clinical course is characterized by variable disease progression. These challenges have hindered the introduction of robust objective biomarkers for patient-specific prediction based on specific phenotypes in clinical practice for patients with DPLD. Therefore, strategies facilitating individualized clinical management, staging and identification of specific phenotypes linked to clinical disease outcomes or therapeutic responses are urgently needed. A classification schema consistently reflecting the radiological, clinical (lung function and clinical outcomes) and pathological features of a disease represents a critical need in modern pulmonary medicine. Herein, we report a quantitative stratification paradigm to identify subsets of DPLD patients with characteristic radiologic patterns in an unsupervised manner and demonstrate significant correlation of these self-organized disease groups with clinically accepted surrogate endpoints. The proposed consistent and reproducible technique could potentially transform diagnostic staging, clinical management and prognostication of DPLD patients as well as facilitate patient selection for clinical trials beyond the ability of current radiological tools. In addition, the sequential quantitative stratification of the type and extent of parenchymal process may allow standardized and objective monitoring of disease, early assessment of treatment response and mortality prediction for DPLD patients. PMID:24676019

A definition for aggressive disease in patients with HER-2 negative metastatic breast cancer: an expert consensus of the Spanish Society of Medical Oncology (SEOM).

PubMed

González, A; Lluch, A; Aba, E; Albanell, J; Antón, A; Álvarez, I; Ayala, F; Barnadas, A; Calvo, L; Ciruelos, E; Cortés, J; de la Haba, J; López-Vega, J M; Martínez, E; Muñoz, M; Peláez, I; Redondo, A; Rodríguez, Á; Rodríguez, C A; Ruíz, A; Llombart, A

2017-05-01

To converge on an expert opinion to define aggressive disease in patients with HER2-negative mBC using a modified Delphi methodology. A panel of 21 breast cancer experts from the Spanish Society of Medical Oncology agreed upon a survey which comprised 47 questions that were grouped into three sections: relevance for defining aggressive disease, aggressive disease criteria and therapeutic goals. Answers were rated using a 9-point Likert scale of relevance or agreement. Among the 88 oncologists that were invited to participate, 81 answered the first round (92%), 70 answered the second round (80%), and 67 answered the third round (76%) of the survey. There was strong agreement regarding the fact that identifying patients with aggressive disease needs to be adequately addressed to help practitioners to decide the best treatment options for patients with HER2-negative mBC. The factors that were considered to be strongly relevant to classifying patients with aggressive HER2-negative mBC were a high tumor burden, a disease-free interval of less than 12-24 months after surgery, the presence of progressive disease during adjuvant or neoadjuvant chemotherapy and having a triple-negative phenotype. The main therapeutic goals were controlling symptoms, improving quality of life and increasing the time to progression and overall survival. High tumor burden, time to recurrence after prior therapy and having a triple-negative phenotype were the prognostic factors for which the greatest consensus was found for identifying patients with aggressive HER2-negative mBC. Identifying patients with aggressive disease leads to different therapeutic approaches.

P21, COX-2, and E-cadherin are potential prognostic factors for esophageal squamous cell carcinoma.

PubMed

Lin, Yao; Shen, Lu-Yan; Fu, Hao; Dong, Bin; Yang, He-Li; Yan, Wan-Pu; Kang, Xiao-Zheng; Dai, Liang; Zhou, Hai-Tao; Yang, Yong-Bo; Liang, Zhen; Chen, Ke-Neng

2017-02-01

Much research effort has been devoted to identifying prognostic factors for esophageal squamous cell carcinoma (ESCC) by immunohistochemistry; however, no conclusive findings have been reached thus far. We hypothesized that certain molecules identified in previous studies might serve as useful prognostic markers for ESCC. Therefore, the aim of the current study was to validate the most relevant markers showing potential for ESCC prognosis in our prospective esophageal cancer database. A literature search was performed using the PubMed database for papers published between 1980 and 2015 using the following key words: 'esophageal cancer,' 'prognosis,' and 'immunohistochemistry.' Literature selection criteria were established to identify the most widely studied markers, and we further validated the selected markers in a cohort from our single-surgeon team, including 153 esophageal cancer patients treated from 2000 to 2010. A total of 1799 articles were identified, 82 of which met the selection criteria. Twelve markers were found to be the most widely studied, and the validation results indicated that only P21, COX-2, and E-cadherin were independent prognostic factors for ESCC patients in this series. The systemic review and cohort validation suggest that P21, COX-2, and E-cadherin are potential prognostic factors for ESCC, paving the way for more targeted prospective validation in the future. © 2016 International Society for Diseases of the Esophagus.

Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model

PubMed Central

Scarisbrick, Julia J.; Prince, H. Miles; Vermeer, Maarten H.; Quaglino, Pietro; Horwitz, Steven; Porcu, Pierluigi; Stadler, Rudolf; Wood, Gary S.; Beylot-Barry, Marie; Pham-Ledard, Anne; Foss, Francine; Girardi, Michael; Bagot, Martine; Michel, Laurence; Battistella, Maxime; Guitart, Joan; Kuzel, Timothy M.; Martinez-Escala, Maria Estela; Estrach, Teresa; Papadavid, Evangelia; Antoniou, Christina; Rigopoulos, Dimitis; Nikolaou, Vassilki; Sugaya, Makoto; Miyagaki, Tomomitsu; Gniadecki, Robert; Sanches, José Antonio; Cury-Martins, Jade; Miyashiro, Denis; Servitje, Octavio; Muniesa, Cristina; Berti, Emilio; Onida, Francesco; Corti, Laura; Hodak, Emilia; Amitay-Laish, Iris; Ortiz-Romero, Pablo L.; Rodríguez-Peralto, Jose L.; Knobler, Robert; Porkert, Stefanie; Bauer, Wolfgang; Pimpinelli, Nicola; Grandi, Vieri; Cowan, Richard; Rook, Alain; Kim, Ellen; Pileri, Alessandro; Patrizi, Annalisa; Pujol, Ramon M.; Wong, Henry; Tyler, Kelly; Stranzenbach, Rene; Querfeld, Christiane; Fava, Paolo; Maule, Milena; Willemze, Rein; Evison, Felicity; Morris, Stephen; Twigger, Robert; Talpur, Rakhshandra; Kim, Jinah; Ognibene, Grant; Li, Shufeng; Tavallaee, Mahkam; Hoppe, Richard T.; Duvic, Madeleine; Whittaker, Sean J.; Kim, Youn H.

2015-01-01

Purpose Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. Patients and Methods Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). Results Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). Conclusion To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients. PMID:26438120

Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model.

PubMed

Scarisbrick, Julia J; Prince, H Miles; Vermeer, Maarten H; Quaglino, Pietro; Horwitz, Steven; Porcu, Pierluigi; Stadler, Rudolf; Wood, Gary S; Beylot-Barry, Marie; Pham-Ledard, Anne; Foss, Francine; Girardi, Michael; Bagot, Martine; Michel, Laurence; Battistella, Maxime; Guitart, Joan; Kuzel, Timothy M; Martinez-Escala, Maria Estela; Estrach, Teresa; Papadavid, Evangelia; Antoniou, Christina; Rigopoulos, Dimitis; Nikolaou, Vassilki; Sugaya, Makoto; Miyagaki, Tomomitsu; Gniadecki, Robert; Sanches, José Antonio; Cury-Martins, Jade; Miyashiro, Denis; Servitje, Octavio; Muniesa, Cristina; Berti, Emilio; Onida, Francesco; Corti, Laura; Hodak, Emilia; Amitay-Laish, Iris; Ortiz-Romero, Pablo L; Rodríguez-Peralto, Jose L; Knobler, Robert; Porkert, Stefanie; Bauer, Wolfgang; Pimpinelli, Nicola; Grandi, Vieri; Cowan, Richard; Rook, Alain; Kim, Ellen; Pileri, Alessandro; Patrizi, Annalisa; Pujol, Ramon M; Wong, Henry; Tyler, Kelly; Stranzenbach, Rene; Querfeld, Christiane; Fava, Paolo; Maule, Milena; Willemze, Rein; Evison, Felicity; Morris, Stephen; Twigger, Robert; Talpur, Rakhshandra; Kim, Jinah; Ognibene, Grant; Li, Shufeng; Tavallaee, Mahkam; Hoppe, Richard T; Duvic, Madeleine; Whittaker, Sean J; Kim, Youn H

2015-11-10

Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients. © 2015 by American Society of Clinical Oncology.

The prognostic value of BRCA1 promoter methylation in early stage triple negative breast cancer

PubMed Central

Kimler, Bruce F.; Sethi, Geetika; Petroff, Brian K.; Phillips, Teresa A.; Tawfik, Ossama W.; Godwin, Andrew K.; Jensen, Roy A.

2014-01-01

Introduction Methylation of the BRCA1 promoter is frequent in triple negative breast cancers (TNBC) and results in a tumor phenotype similar to BRCA1-mutated tumors. BRCA1 mutation-associated cancers are more sensitive to DNA damaging agents as compared to conventional chemotherapy agents. It is not known if there is an interaction between the presence of BRCA1 promoter methylation (PM) and response to chemotherapy agents in sporadic TNBC. We sought to investigate the prognostic significance of BRCA1 PM in TNBC patients receiving standard chemotherapy. Methods Subjects with stage I-III TNBC treated with chemotherapy were identified and their formalin-fixed paraffin-embedded (FFPE) tumor specimens retrieved. Genomic DNA was isolated and subjected to methylation-specific PCR (MSPCR). Results DNA was isolated from primary tumor of 39 subjects. BRCA1 PM was detected in 30% of patients. Presence of BRCA1 PM was associated with lower BRCA1 transcript levels, suggesting epigenetic BRCA1 silencing. All patients received chemotherapy (anthracycline:90%, taxane:69%). At a median follow-up of 64 months, 46% of patients have recurred and 36% have died. On univariate analysis, African-American race, node positivity, stage, and BRCA1 PM were associated with worse RFS and OS. Five year OS was 36% for patients with BRCA1 PM vs. 77% for patients without BRCA1 PM (p=0.004). On multivariable analysis, BRCA1 PM was associated with significantly worse RFS and OS. Conclusions We show that BRCA1 PM is common in TNBC and has the potential to identify a significant fraction of TNBC patients who have suboptimal outcomes with standard chemotherapy. PMID:25177489

Rational bases for the use of the Immunoscore in routine clinical settings as a prognostic and predictive biomarker in cancer patients

PubMed Central

Kirilovsky, Amos; Marliot, Florence; El Sissy, Carine; Haicheur, Nacilla; Galon, Jérôme

2016-01-01

The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) tumor, nodes, metastasis (TNM) classification system based on tumor features is used for prognosis estimation and treatment recommendations in most cancers. However, the clinical outcome can vary significantly among patients within the same tumor stage and TNM classification does not predict response to therapy. Therefore, many efforts have been focused on the identification of new markers. Multiple tumor cell-based approaches have been proposed but very few have been translated into the clinic. The recent demonstration of the essential role of the immune system in tumor progression has allowed great advances in the understanding of this complex disease and in the design of novel therapies. The analysis of the immune infiltrate by imaging techniques in large patient cohorts highlighted the prognostic impact of the in situ immune cell infiltrate in tumors. Moreover, the characterization of the immune infiltrates (e.g. type, density, distribution within the tumor, phenotype, activation status) in patients treated with checkpoint-blockade strategies could provide information to predict the disease outcome. In colorectal cancer, we have developed a prognostic score (‘Immunoscore’) that takes into account the distribution of the density of both CD3+ lymphocytes and CD8+ cytotoxic T cells in the tumor core and the invasive margin that could outperform TNM staging. Currently, an international retrospective study is under way to validate the Immunoscore prognostic performance in patients with colon cancer. The use of Immunoscore in clinical practice could improve the patients’ prognostic assessment and therapeutic management. PMID:27121213

Three-Gene Immunohistochemical Panel Adds to Clinical Staging Algorithms to Predict Prognosis for Patients With Esophageal Adenocarcinoma

PubMed Central

Ong, Chin-Ann J.; Shapiro, Joel; Nason, Katie S.; Davison, Jon M.; Liu, Xinxue; Ross-Innes, Caryn; O'Donovan, Maria; Dinjens, Winand N.M.; Biermann, Katharina; Shannon, Nicholas; Worster, Susannah; Schulz, Laura K.E.; Luketich, James D.; Wijnhoven, Bas P.L.; Hardwick, Richard H.; Fitzgerald, Rebecca C.

2013-01-01

Purpose Esophageal adenocarcinoma (EAC) is a highly aggressive disease with poor long-term survival. Despite growing knowledge of its biology, no molecular biomarkers are currently used in routine clinical practice to determine prognosis or aid clinical decision making. Hence, this study set out to identify and validate a small, clinically applicable immunohistochemistry (IHC) panel for prognostication in patients with EAC. Patients and Methods We recently identified eight molecular prognostic biomarkers using two different genomic platforms. IHC scores of these biomarkers from a UK multicenter cohort (N = 374) were used in univariate Cox regression analysis to determine the smallest biomarker panel with the greatest prognostic power with potential therapeutic relevance. This new panel was validated in two independent cohorts of patients with EAC who had undergone curative esophagectomy from the United States and Europe (N = 666). Results Three of the eight previously identified prognostic molecular biomarkers (epidermal growth factor receptor [EGFR], tripartite motif-containing 44 [TRIM44], and sirtuin 2 [SIRT2]) had the strongest correlation with long-term survival in patients with EAC. Applying these three biomarkers as an IHC panel to the validation cohort segregated patients into two different prognostic groups (P < .01). Adjusting for known survival covariates, including clinical staging criteria, the IHC panel remained an independent predictor, with incremental adverse overall survival (OS) for each positive biomarker (hazard ratio, 1.20; 95% CI, 1.03 to 1.40 per biomarker; P = .02). Conclusion We identified and validated a clinically applicable IHC biomarker panel, consisting of EGFR, TRIM44, and SIRT2, that is independently associated with OS and provides additional prognostic information to current survival predictors such as stage. PMID:23509313

Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis-Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer.

PubMed

Kimbung, Siker; Johansson, Ida; Danielsson, Anna; Veerla, Srinivas; Egyhazi Brage, Suzanne; Frostvik Stolt, Marianne; Skoog, Lambert; Carlsson, Lena; Einbeigi, Zakaria; Lidbrink, Elisabet; Linderholm, Barbro; Loman, Niklas; Malmström, Per-Olof; Söderberg, Martin; Walz, Thomas M; Fernö, Mårten; Hatschek, Thomas; Hedenfalk, Ingrid

2016-01-01

The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis-selective genes of prognostic importance following primary tumor diagnosis. A cohort of 304 women with advanced breast cancer was studied. Associations between the site of recurrence and clinicopathologic features were investigated. Fine-needle aspirates of metastases (n = 91) were subjected to whole-genome transcriptional profiling. Liver metastasis-selective genes were identified by significance analysis of microarray (SAM) analyses and independently validated in external datasets. Finally, the prognostic relevance of the liver metastasis-selective genes in primary breast cancer was tested. Liver relapse was associated with estrogen receptor (ER) expression (P = 0.002), luminal B subtype (P = 0.01), and was prognostic for an inferior postrelapse survival (P = 0.01). The major variation in the transcriptional landscape of metastases was also associated with ER expression and molecular subtype. However, liver metastases displayed unique transcriptional fingerprints, characterized by downregulation of extracellular matrix (i.e., stromal) genes. Importantly, we identified a 17-gene liver metastasis-selective signature, which was significantly and independently prognostic for shorter relapse-free (P < 0.001) and overall (P = 0.001) survival in ER-positive tumors. Remarkably, this signature remained independently prognostic for shorter relapse-free survival (P = 0.001) among luminal A tumors. Extracellular matrix (stromal) genes can be used to partition breast cancer by site of relapse and may be used to further refine prognostication in ER positive primary breast cancer. ©2015 American Association for Cancer Research.

Early speech development in Koolen de Vries syndrome limited by oral praxis and hypotonia.

PubMed

Morgan, Angela T; Haaften, Leenke van; van Hulst, Karen; Edley, Carol; Mei, Cristina; Tan, Tiong Yang; Amor, David; Fisher, Simon E; Koolen, David A

2018-01-01

Communication disorder is common in Koolen de Vries syndrome (KdVS), yet its specific symptomatology has not been examined, limiting prognostic counselling and application of targeted therapies. Here we examine the communication phenotype associated with KdVS. Twenty-nine participants (12 males, 4 with KANSL1 variants, 25 with 17q21.31 microdeletion), aged 1.0-27.0 years were assessed for oral-motor, speech, language, literacy, and social functioning. Early history included hypotonia and feeding difficulties. Speech and language development was delayed and atypical from onset of first words (2; 5-3; 5 years of age on average). Speech was characterised by apraxia (100%) and dysarthria (93%), with stuttering in some (17%). Speech therapy and multi-modal communication (e.g., sign-language) was critical in preschool. Receptive and expressive language abilities were typically commensurate (79%), both being severely affected relative to peers. Children were sociable with a desire to communicate, although some (36%) had pragmatic impairments in domains, where higher-level language was required. A common phenotype was identified, including an overriding 'double hit' of oral hypotonia and apraxia in infancy and preschool, associated with severely delayed speech development. Remarkably however, speech prognosis was positive; apraxia resolved, and although dysarthria persisted, children were intelligible by mid-to-late childhood. In contrast, language and literacy deficits persisted, and pragmatic deficits were apparent. Children with KdVS require early, intensive, speech motor and language therapy, with targeted literacy and social language interventions as developmentally appropriate. Greater understanding of the linguistic phenotype may help unravel the relevance of KANSL1 to child speech and language development.

Treatment-Related Predictive and Prognostic Factors in Trimodality Approach in Stage IIIA/N2 Non-Small Cell Lung Cancer.

PubMed

Jeremić, Branislav; Casas, Francesc; Dubinsky, Pavol; Gomez-Caamano, Antonio; Čihorić, Nikola; Videtic, Gregory; Igrutinovic, Ivan

2018-01-01

While there are no established pretreatment predictive and prognostic factors in patients with stage IIIA/pN2 non-small cell lung cancer (NSCLC) indicating a benefit to surgery as a part of trimodality approach, little is known about treatment-related predictive and prognostic factors in this setting. A literature search was conducted to identify possible treatment-related predictive and prognostic factors for patients for whom trimodality approach was reported on. Overall survival was the primary endpoint of this study. Of 30 identified studies, there were two phase II studies, 5 "prospective" studies, and 23 retrospective studies. No study was found which specifically looked at treatment-related predictive factors of improved outcomes in trimodality treatment. Of potential treatment-related prognostic factors, the least frequently analyzed factors among 30 available studies were overall pathologic stage after preoperative treatment and UICC downstaging. Evaluation of treatment response before surgery and by pathologic tumor stage after induction therapy were analyzed in slightly more than 40% of studies and found not to influence survival. More frequently studied factors-resection status, degree of tumor regression, and pathologic nodal stage after induction therapy as well as the most frequently studied factor, the treatment (in almost 75% studies)-showed no discernible impact on survival, due to conflicting results. Currently, it is impossible to identify any treatment-related predictive or prognostic factors for selecting surgery in the treatment of patients with stage IIIA/pN2 NSCLC.

Prognostic Factors for Recovery After Anterior Debridement/Bone Grafting and Posterior Instrumentation for Lumbar Spinal Tuberculosis.

PubMed

Yao, Yuan; Zhang, Huiyu; Liu, Huan; Zhang, Zhengfeng; Tang, Yu; Zhou, Yue

2017-08-01

Anterior debridement/bone grafting/posterior instrumentation is a common selection for the treatment of lumbar spinal tuberculosis (LST). To date, no study has focused on the prognostic factors for recovery after this surgery. We included 144 patients who experienced anterior debridement/bone grafting/posterior instrumentation for LST. The recovery rate based on the Japanese Orthopedic Association (JOA) score was used to assess recovery. The Kaplan-Meier method and Cox regression analysis were used to identify the prognostic factors for recovery postoperatively. For the prognostic factors worth further consideration, the changes in JOA scores within the 24-month follow-up period were identified by repeated-measures analysis of variance. Paralysis/nonparalysis, duration of symptoms (≥3/<3 months), number of involved vertebrae (>2/≤2), and posterior open/percutaneous instrumentation were identified as prognostic factors for recovery postoperatively. The prognostic factor of open/percutaneous instrumentation was then further compared for potential clinical application. Patients in the percutaneous instrumentation group achieved higher JOA scores than those in the open instrumentation group in the early stages postoperatively (1-3 months), but this effect equalized at 6 months postoperatively. Patients in the open instrumentation group experienced longer operation time and less cost than those in the percutaneous instrumentation group. Nonparalysis, shorter symptom duration, fewer involved vertebrae, and posterior percutaneous instrumentation (compared with open instrumentation) are considered favorable prognostic factors. Patients in the percutaneous instrumentation group achieved higher JOA scores than those in the open instrumentation group in the early stages postoperatively (1-3 months), but no significant difference was observed in long-term JOA scores (6-24 months). Copyright © 2017. Published by Elsevier Inc.

Serum amyloid A as a prognostic marker in melanoma identified by proteomic profiling.

PubMed

Findeisen, Peter; Zapatka, Marc; Peccerella, Teresa; Matzk, Heike; Neumaier, Michael; Schadendorf, Dirk; Ugurel, Selma

2009-05-01

Currently known prognostic serum biomarkers of melanoma are powerful in metastatic disease, but weak in early-stage patients. This study was aimed to identify new prognostic biomarkers of melanoma by serum mass spectrometry (MS) proteomic profiling, and to validate candidates compared with established markers. Two independent sets of serum samples from 596 melanoma patients were investigated. The first set (stage I = 102; stage IV = 95) was analyzed by matrix assisted laser desorption and ionization time of flight (MALDI TOF) MS for biomarkers differentiating between stage I and IV. In the second set (stage I = 98; stage II = 91; stage III = 87; stage IV = 103), the serum concentrations of the candidate marker serum amyloid A (SAA) and the known biomarkers S100B, lactate dehydrogenase, and C reactive protein (CRP) were measured using immunoassays. MALDI TOF MS revealed a peak at m/z 11.680 differentiating between stage I and IV, which could be identified as SAA. High peak intensities at m/z 11.680 correlated with poor survival. In univariate analysis, SAA was a strong prognostic marker in stage I to III (P = .043) and stage IV (P = .000083) patients. Combination of SAA and CRP increased the prognostic impact to P = .011 in early-stage (I to III) patients. Multivariate analysis revealed sex, stage, tumor load, S100B, SAA, and CRP as independent prognostic factors, with an interaction between SAA and CRP. In stage I to III patients, SAA combined with CRP was superior to S100B in predicting patients' progression-free and overall survival. SAA combined with CRP might be used as prognostic serological biomarkers in early-stage melanoma patients, helping to discriminate low-risk patients from high-risk patients needing adjuvant treatment.

Investigating a multigene prognostic assay based on significant pathways for Luminal A breast cancer through gene expression profile analysis.

PubMed

Gao, Haiyan; Yang, Mei; Zhang, Xiaolan

2018-04-01

The present study aimed to investigate potential recurrence-risk biomarkers based on significant pathways for Luminal A breast cancer through gene expression profile analysis. Initially, the gene expression profiles of Luminal A breast cancer patients were downloaded from The Cancer Genome Atlas database. The differentially expressed genes (DEGs) were identified using a Limma package and the hierarchical clustering analysis was conducted for the DEGs. In addition, the functional pathways were screened using Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and rank ratio calculation. The multigene prognostic assay was exploited based on the statistically significant pathways and its prognostic function was tested using train set and verified using the gene expression data and survival data of Luminal A breast cancer patients downloaded from the Gene Expression Omnibus. A total of 300 DEGs were identified between good and poor outcome groups, including 176 upregulated genes and 124 downregulated genes. The DEGs may be used to effectively distinguish Luminal A samples with different prognoses verified by hierarchical clustering analysis. There were 9 pathways screened as significant pathways and a total of 18 DEGs involved in these 9 pathways were identified as prognostic biomarkers. According to the survival analysis and receiver operating characteristic curve, the obtained 18-gene prognostic assay exhibited good prognostic function with high sensitivity and specificity to both the train and test samples. In conclusion the 18-gene prognostic assay including the key genes, transcription factor 7-like 2, anterior parietal cortex and lymphocyte enhancer factor-1 may provide a new method for predicting outcomes and may be conducive to the promotion of precision medicine for Luminal A breast cancer.

Symptomatic spinal metastasis: A systematic literature review of the preoperative prognostic factors for survival, neurological, functional and quality of life in surgically treated patients and methodological recommendations for prognostic studies

PubMed Central

Nater, Anick; Martin, Allan R.; Sahgal, Arjun; Choi, David

2017-01-01

Purpose While several clinical prediction rules (CPRs) of survival exist for patients with symptomatic spinal metastasis (SSM), these have variable prognostic ability and there is no recognized CPR for health related quality of life (HRQoL). We undertook a critical appraisal of the literature to identify key preoperative prognostic factors of clinical outcomes in patients with SSM who were treated surgically. The results of this study could be used to modify existing or develop new CPRs. Methods Seven electronic databases were searched (1990–2015), without language restriction, to identify studies that performed multivariate analysis of preoperative predictors of survival, neurological, functional and HRQoL outcomes in surgical patients with SSM. Individual studies were assessed for class of evidence. The strength of the overall body of evidence was evaluated using GRADE for each predictor. Results Among 4,818 unique citations, 17 were included; all were in English, rated Class III and focused on survival, revealing a total of 46 predictors. The strength of the overall body of evidence was very low for 39 and low for 7 predictors. Due to considerable heterogeneity in patient samples and prognostic factors investigated as well as several methodological issues, our results had a moderately high risk of bias and were difficult to interpret. Conclusions The quality of evidence for predictors of survival was, at best, low. We failed to identify studies that evaluated preoperative prognostic factors for neurological, functional, or HRQoL outcomes in surgical patients with SSM. We formulated methodological recommendations for prognostic studies to promote acquiring high-quality evidence to better estimate predictor effect sizes to improve patient education, surgical decision-making and development of CPRs. PMID:28225772

The importance of histopathological and clinical variables in predicting the evolution of colon cancer.

PubMed

Diculescu, Mircea; Iacob, Răzvan; Iacob, Speranţa; Croitoru, Adina; Becheanu, Gabriel; Popeneciu, Valentin

2002-09-01

It has been a consensus that prognostic factors should always be taken into account before planning treatment in colorectal cancer. A 5 year prospective study was conducted, in order to assess the importance of several histopathological and clinical prognostic variables in the prediction of evolution in colon cancer. Some of the factors included in the analysis are still subject to dispute by different authors. 46 of 53 screened patients qualified to enter the study and underwent a potentially curative resection of the tumor, followed, when necessary, by adjuvant chemotherapy. Univariate and multivariate analyses were carried out in order to identify independent prognostic indicators. The endpoint of the study was considered the recurrence of the tumor or the detection of metastases. 65.2% of the patients had a good evolution during the follow up period. Multivariate survival analysis performed by Cox proportional hazard model identified 3 independent prognostic factors: Dukes stage (p = 0.00002), the grade of differentiation (p = 0.0009) and the weight loss index, representing the weight loss of the patient divided by the number of months when it was actually lost (p = 0.02). Age under 40 years, sex, microscopic aspect of the tumor, tumor location, anemia degree were not identified by our analysis as having prognostic importance. Histopathological factors continue to be the most valuable source of information regarding the possible evolution of patients with colorectal cancer. Individual clinical symptoms or biological parameters such as erytrocyte sedimentation rate or hemoglobin level are of little or no prognostic value. More research is required relating to the impact of a performance status index (which could include also weight loss index) as another reliable prognostic variable.

Prognostic indices for early mortality in ischaemic stroke - meta-analysis.

PubMed

Mattishent, K; Kwok, C S; Mahtani, A; Pelpola, K; Myint, P K; Loke, Y K

2016-01-01

Several models have been developed to predict mortality in ischaemic stroke. We aimed to evaluate systematically the performance of published stroke prognostic scores. We searched MEDLINE and EMBASE in February 2014 for prognostic models (published between 2003 and 2014) used in predicting early mortality (<6 months) after ischaemic stroke. We evaluated discriminant ability of the tools through meta-analysis of the area under the curve receiver operating characteristic curve (AUROC) or c-statistic. We evaluated the following components of study validity: collection of prognostic variables, neuroimaging, treatment pathways and missing data. We identified 18 articles (involving 163 240 patients) reporting on the performance of prognostic models for mortality in ischaemic stroke, with 15 articles providing AUC for meta-analysis. Most studies were either retrospective, or post hoc analyses of prospectively collected data; all but three reported validation data. The iSCORE had the largest number of validation cohorts (five) within our systematic review and showed good performance in four different countries, pooled AUC 0.84 (95% CI 0.82-0.87). We identified other potentially useful prognostic tools that have yet to be as extensively validated as iSCORE - these include SOAR (2 studies, pooled AUC 0.79, 95% CI 0.78-0.80), GWTG (2 studies, pooled AUC 0.72, 95% CI 0.72-0.72) and PLAN (1 study, pooled AUC 0.85, 95% CI 0.84-0.87). Our meta-analysis has identified and summarized the performance of several prognostic scores with modest to good predictive accuracy for early mortality in ischaemic stroke, with the iSCORE having the broadest evidence base. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ways of providing the patient with a prognosis: a terminology of employed strategies based on qualitative data.

PubMed

Graugaard, Peter Kjær; Rogg, Lotte; Eide, Hilde; Uhlig, Till; Loge, Jon Håvard

2011-04-01

To identify, denote, and structure strategies applied by physicians and patients when communicating information about prognosis. A descriptive qualitative study based on audiotaped physician-patient encounters between 23 haematologists and rheumatologists, and 89 patients in Oslo. Classification of identified prognostic sequences was based on consensus. Physicians seldom initiated communication with patients explicitly to find out their overall preferences for prognostic information (metacommunication). Instead, they used sounding and implicit strategies such as invitations, implicatures, and non-specific information that might result in further disclosure of information if requested by the patients. In order to balance the obligation to promote hope and provide (true) information, they used strategies such as bad news/good news spirals, authentications, safeguardings, and softenings. Identified strategies applied by the patients to adjust the physician-initiated prognostic information to their needs were requests for specification, requests for optimism, and emotional warnings. The study presents an empirically derived terminology so that clinicians and educators involved in medical communication can increase their awareness of prognostic communication. Based on qualitative data obtained from communication excerpts, we suggest that individual clinicians and researchers evaluate the possible benefits of more frequent use of metacommunication and explicit prognostic information. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

The role of advanced echocardiography and cardiovascular magnetic resonance in the assessment of myocardial function in Marfan syndrome-An update.

PubMed

Kiotsekoglou, Anatoli; Moggridge, James C; Child, Anne H; Rask, Peter

2017-05-01

Cardiovascular assessment of patients with Marfan syndrome has normally focused on the aortic root and vascular manifestations of the disease due to the high risk of aortic dissection. Although primary myocardial impairment has long been suspected in these patients, the evidence has been controversial. Advanced echocardiography and cardiovascular magnetic resonance imaging have proven to be effective, accurate, and more sensitive in the detection of subtle cardiac dysfunction. The application of these techniques to Marfan syndrome over the last 10 years has made significant progress in demonstrating the presence of primary myocardial impairment in these patients, but further work is still required to obtain confirmatory molecular, pathophysiological, and prognostic clinical data. Phenotypic expression of the disease has prognostic value, also suggesting potential effective medical therapy. © 2017, Wiley Periodicals, Inc.

Combined evaluation of the FAS cell surface death receptor and CD8+ tumor infiltrating lymphocytes as a prognostic biomarker in breast cancer

PubMed Central

Blok, Erik J.; van den Bulk, Jitske; Dekker-Ensink, N. Geeske; Derr, Remco; Kanters, Corné; Bastiaannet, Esther; Kroep, Judith R.; van de Velde, Cornelis J.H.; Kuppen, Peter J.K.

2017-01-01

Multiple studies showed the prognostic capacities of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), but not in other subtypes. We evaluated tumor expression of FAS, a key receptor in T-cell mediated apoptosis, as possible explanation for this differential prognostic value of TILs. Furthermore, we evaluated the prognostic relevance of FAS, both as an independent biomarker and in relation to CD8-positive T-cell presence. The study cohort consisted of 667 breast cancer patients treated in the LUMC between 1997 and 2009. FAS expression was determined using immunohistochemistry and the percentage of FAS-positive tumor cells was quantified. Furthermore, the number of CD8-positive infiltrating cells was determined, and its prognostic relevance was associated to FAS-expression using stratified survival analysis. In TNBC, FAS was averagely expressed in 49% of tumor cells, whereas ER-positive subtypes showed an average Fas expression of 16-20%. In the entire cohort, FAS was identified as significant prognostic marker for recurrence (adjusted HR 0.53, 95% CI 0.36-0.77) and borderline significant marker for overall survival (adjusted HR 0.72, 95% CI 0.52-1.01). Upon stratification for FAS-expression, CD8+ TILs were only prognostic at high levels (above median) of FAS expression in ER-negative disease. In summary, FAS was identified as an independent prognostic marker for recurrence free survival in breast cancer, with large variation in expression by receptor subtypes. Interestingly, the prognostic effect of CD8+ TILs in ER-negative disease was only valid for tumors with a high FAS expression. PMID:28121628

Combined evaluation of the FAS cell surface death receptor and CD8+ tumor infiltrating lymphocytes as a prognostic biomarker in breast cancer.

PubMed

Blok, Erik J; van den Bulk, Jitske; Dekker-Ensink, N Geeske; Derr, Remco; Kanters, Corné; Bastiaannet, Esther; Kroep, Judith R; van de Velde, Cornelis J H; Kuppen, Peter J K

2017-02-28

Multiple studies showed the prognostic capacities of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), but not in other subtypes. We evaluated tumor expression of FAS, a key receptor in T-cell mediated apoptosis, as possible explanation for this differential prognostic value of TILs. Furthermore, we evaluated the prognostic relevance of FAS, both as an independent biomarker and in relation to CD8-positive T-cell presence. The study cohort consisted of 667 breast cancer patients treated in the LUMC between 1997 and 2009. FAS expression was determined using immunohistochemistry and the percentage of FAS-positive tumor cells was quantified. Furthermore, the number of CD8-positive infiltrating cells was determined, and its prognostic relevance was associated to FAS-expression using stratified survival analysis. In TNBC, FAS was averagely expressed in 49% of tumor cells, whereas ER-positive subtypes showed an average Fas expression of 16-20%. In the entire cohort, FAS was identified as significant prognostic marker for recurrence (adjusted HR 0.53, 95% CI 0.36-0.77) and borderline significant marker for overall survival (adjusted HR 0.72, 95% CI 0.52-1.01). Upon stratification for FAS-expression, CD8+ TILs were only prognostic at high levels (above median) of FAS expression in ER-negative disease. In summary, FAS was identified as an independent prognostic marker for recurrence free survival in breast cancer, with large variation in expression by receptor subtypes. Interestingly, the prognostic effect of CD8+ TILs in ER-negative disease was only valid for tumors with a high FAS expression.

Prognostic value of baseline seric Syndecan-1 in initially unresectable metastatic colorectal cancer patients: a simple biological score.

PubMed

Jary, Marine; Lecomte, Thierry; Bouché, Olivier; Kim, Stefano; Dobi, Erion; Queiroz, Lise; Ghiringhelli, Francois; Etienne, Hélène; Léger, Julie; Godet, Yann; Balland, Jérémy; Lakkis, Zaher; Adotevi, Olivier; Bonnetain, Franck; Borg, Christophe; Vernerey, Dewi

2016-11-15

In first-line metastatic colorectal cancer (mCRC), baseline prognostic factors allowing death risk and treatment strategy stratification are lacking. Syndecan-1 (CD138) soluble form was never described as a prognostic biomarker in mCRC. We investigated its additional prognostic value for overall survival (OS). mCRC patients with unresectable disease at diagnosis were treated with bevacizumab-based chemotherapy in two independent prospective clinical trials (development set: n = 126, validation set: n = 51, study NCT00489697 and study NCT00544011, respectively). Serums were collected at baseline for CD138 measurement. OS determinants were assessed and, based on the final multivariate model, a prognostic score was proposed. Two independent OS prognostic factors were identified: Lactate Dehydrogenase (LDH) high level (p = 0.0066) and log-CD138 high level (p = 0.0190). The determination of CD138 binary information (cutoff: 75 ng/mL) allowed the assessment of a biological prognostic score with CD138 and LDH values, identifying three risk groups for death (median OS= 38.9, 30.1 and 19.8 months for the low, intermediate and high risk groups, respectively; p < 0.0001). This score had a good discrimination ability (C-index = 0.63). These results were externally confirmed in the validation set. Our study provides robust evidence in favor of the additional baseline soluble CD138 prognostic value for OS, in mCRC patients. A simple biological scoring system is proposed including LDH and CD138 binary status values. © 2016 UICC.

Prognostic model based on nailfold capillaroscopy for identifying Raynaud's phenomenon patients at high risk for the development of a scleroderma spectrum disorder: PRINCE (prognostic index for nailfold capillaroscopic examination).

PubMed

Ingegnoli, Francesca; Boracchi, Patrizia; Gualtierotti, Roberta; Lubatti, Chiara; Meani, Laura; Zahalkova, Lenka; Zeni, Silvana; Fantini, Flavio

2008-07-01

To construct a prognostic index based on nailfold capillaroscopic examinations that is capable of predicting the 5-year transition from isolated Raynaud's phenomenon (RP) to RP secondary to scleroderma spectrum disorders (SSDs). The study involved 104 consecutive adult patients with a clinical history of isolated RP, and the index was externally validated in another cohort of 100 patients with the same characteristics. Both groups were followed up for 1-8 years. Six variables were examined because of their potential prognostic relevance (branching, enlarged and giant loops, capillary disorganization, microhemorrhages, and the number of capillaries). The only factors that played a significant prognostic role were the presence of giant loops (hazard ratio [HR] 2.64, P = 0.008) and microhemorrhages (HR 2.33, P = 0.01), and the number of capillaries (analyzed as a continuous variable). The adjusted prognostic role of these factors was evaluated by means of multivariate regression analysis, and the results were used to construct an algorithm-based prognostic index. The model was internally and externally validated. Our prognostic capillaroscopic index identifies RP patients in whom the risk of developing SSDs is high. This model is a weighted combination of different capillaroscopy parameters that allows physicians to stratify RP patients easily, using a relatively simple diagram to deduce the prognosis. Our results suggest that this index could be used in clinical practice, and its further inclusion in prospective studies will undoubtedly help in exploring its potential in predicting treatment response.

Newly identified poor prognostic factors for adult T-cell leukemia-lymphoma treated with allogeneic hematopoietic stem cell transplantation.

PubMed

Tokunaga, Masahito; Uto, Hirofumi; Takeuchi, Shogo; Nakano, Nobuaki; Kubota, Ayumu; Tokunaga, Mayumi; Takatsuka, Yoshifusa; Seto, Masao; Ido, Akio; Utsunomiya, Atae

2017-01-01

To explore pre-transplantation prognostic factors for adult T-cell leukemia-lymphoma (ATL), we retrospectively analyzed allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 70 patients at our institute (63 acute type and seven lymphoma type patients). Forty-five patients died after HSCT and the three-year overall survival (OS) rate was 35.2%. By univariate analysis, the adverse prognostic factors for OS were performance status ≥2, hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score ≥3, European Group for Blood and Marrow Transplantation (EBMT) risk score ≥5, HSCT from an HLA-mismatched donor, serum soluble interleukin-2 receptor (sIL-2R) level ≥10,000 U/mL, lymphocyte count ≥4000/μL, and hemoglobin <9 g/dL at the time of HSCT. EBMT risk score and sIL-2R were identified as significant adverse prognostic factors using multivariate analysis. This analysis clearly demonstrates for the first time that HCT-CI and EBMT risk scores are reliable prognostic factors for ATL patients receiving allo-HSCT.

Prognostic factors in children with acute myeloid leukaemia and excellent response to remission induction therapy.

PubMed

Karol, Seth E; Coustan-Smith, Elaine; Cao, Xueyuan; Shurtleff, Sheila A; Raimondi, Susana C; Choi, John K; Ribeiro, Raul C; Dahl, Gary V; Bowman, William Paul; Taub, Jeffrey W; Degar, Barbara; Leung, Wing; Downing, James R; Pui, Ching-Hon; Rubnitz, Jeffrey E; Campana, Dario; Inaba, Hiroto

2015-01-01

Minimal residual disease (MRD) is a strong prognostic factor in children and adolescents with acute myeloid leukaemia (AML) but nearly one-quarter of patients who achieve MRD-negative status still relapse. The adverse prognostic factors among MRD-negative patients remain unknown. We analysed the AML02 study cohort to identify demographic and genetic prognostic factors. Among the presenting features, certain 11q23 abnormalities, such as t(6;11) and t(10;11), acute megakaryoblastic leukaemia without the t(1;22), and age ≥10 years were associated with inferior outcome in patients who had MRD-negative status after either remission induction I or II. By contrast, those with rearrangement of CBF genes had superior outcome. Our study identifies patient populations for whom close post-remission MRD monitoring to detect and treat emerging relapse and adjustment in treatment intensity might be indicated. © 2014 John Wiley & Sons Ltd.

PROSPECT: Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

DTIC Science & Technology

2012-06-01

neoadjuvant therapies on disease-free, progression-free, and overall survival will vary across prognostically distinct groups. 3. Specific molecular... prognostically distinct subpopulations of patients with resectable NSCLC, and to assess the extent to which these molecular profiles correlate with tumor...overall survival, and will use Cox proportional hazards models and recursive partitioning methods to identify important biomarkers and prognostically

Aquaporin 1 expression is associated with response to adjuvant chemotherapy in stage II and III colorectal cancer.

PubMed

Imaizumi, Hideko; Ishibashi, Keiichiro; Takenoshita, Seiichi; Ishida, Hideyuki

2018-05-01

Aquaporin 1 (AQP1), which functions as a water transporter, is associated with cancer cell proliferation, invasion, metastasis and angiogenesis in numerous types of solid cancer, including colorectal cancer (CRC). The focus of the present study was to address the potential clinical use of AQP1 expression in CRC as a prognostic and predictive biomarker for disease recurrence and therapeutic outcomes. The current study investigated the expression of AQP1 in surgically resected specimens from 268 patients with stage 0-IV CRC. AQP1 expression was positive in 112 (41.8%) patients, and was significantly associated with left-sided tumors (P<0.01) and with aggressive tumor phenotypes, including depth of invasion (P=0.03), lymph node metastasis (P=0.03), lymphatic invasion (P<0.01) and venous invasion (P<0.01). However, AQP1 expression had no significant prognostic effect on disease-free survival (DFS) in patients with stage II and III CRC following curative surgery. In 84 stage II and III patients who were administered 5-fluorouracil-based adjuvant chemotherapy, positive AQP1 expression was associated with an increased DFS rate compared with that of AQP1-negative patients (P=0.05). Additionally, these results identified that receiving adjuvant chemotherapy was not beneficial to patients with AQP1-negative tumors. This suggests that the expression of AQP1 may be a candidate biomarker predictive of response to 5-fluorouracil-based adjuvant chemotherapy following surgery in patients with stage II and III CRC.

Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer.

PubMed

Jorissen, Robert N; Christie, Michael; Mouradov, Dmitri; Sakthianandeswaren, Anuratha; Li, Shan; Love, Christopher; Xu, Zheng-Zhou; Molloy, Peter L; Jones, Ian T; McLaughlin, Stephen; Ward, Robyn L; Hawkins, Nicholas J; Ruszkiewicz, Andrew R; Moore, James; Burgess, Antony W; Busam, Dana; Zhao, Qi; Strausberg, Robert L; Lipton, Lara; Desai, Jayesh; Gibbs, Peter; Sieber, Oliver M

2015-09-15

APC mutations (APC-mt) occur in ∼70% of colorectal cancers (CRCs), but their relationship to prognosis is unclear. APC prognostic value was evaluated in 746 stage I-IV CRC patients, stratifying for tumour location and microsatellite instability (MSI). Microarrays were used to identify a gene signature that could classify APC mutation status, and classifier ability to predict prognosis was examined in an independent cohort. Wild-type APC microsatellite stable (APC-wt/MSS) tumours from the proximal colon showed poorer overall and recurrence-free survival (OS, RFS) than APC-mt/MSS proximal, APC-wt/MSS distal and APC-mt/MSS distal tumours (OS HR⩾1.79, P⩽0.015; RFS HR⩾1.88, P⩽0.026). APC was a stronger prognostic indicator than BRAF, KRAS, PIK3CA, TP53, CpG island methylator phenotype or chromosomal instability status (P⩽0.036). Microarray analysis similarly revealed poorer survival in MSS proximal cancers with an APC-wt-like signature (P=0.019). APC status did not affect outcomes in MSI tumours. In a validation on 206 patients with proximal colon cancer, APC-wt-like signature MSS cases showed poorer survival than APC-mt-like signature MSS or MSI cases (OS HR⩾2.50, P⩽0.010; RFS HR⩾2.14, P⩽0.025). Poor prognosis APC-wt/MSS proximal tumours exhibited features of the sessile serrated neoplasia pathway (P⩽0.016). APC-wt status is a marker of poor prognosis in MSS proximal colon cancer.

Impact of socioeconomic status on disease phenotype, genomic landscape and outcomes in myelodysplastic syndromes.

PubMed

Mastaglio, Francesca; Bedair, Khaled; Papaemmanuil, Elli; Groves, Michael J; Hyslop, Ann; Keenan, Norene; Hothersall, Eleanor J; Campbell, Peter J; Bowen, David T; Tauro, Sudhir

2016-07-01

Genetic and epigenetic alterations contribute to the biological and clinical characteristics of myelodysplastic syndromes (MDS), but a role for socioeconomic environment remains unclear. Here, socioeconomic status (SES) for 283 MDS patients was estimated using the Scottish Index of Multiple Deprivation tool. Indices were assigned to quintile categorical indicators ranked from SES1 (lowest) to SES5 (highest). Clinicopathological features and outcomes between SES quintiles containing 15%, 20%, 19%, 30% and 16% of patients were compared. Prognostic scores identified lower-risk MDS in 82% of patients, with higher-risk disease in 18%. SES quintiles did not associate with age, gender, cytogenetics, International Prognostic scores or, in sub-analysis (n = 95), driver mutations. The odds ratio of a diagnosis of refractory anaemia was greater than other MDS sub-types in SES5 (OR 1·9, P = 0·024). Most patients (91%) exclusively received supportive care. SES did not associate with leukaemic transformation or cause of death. Cox regression models confirmed male gender (P < 0·05), disease-risk (P < 0·0001) and age (P < 0·01) as independent predictors of leukaemia-free survival, with leukaemic transformation an additional determinant of overall survival (P = 0·07). Thus, if access to healthcare is equitable, SES does not determine disease biology or survival in MDS patients receiving supportive treatment; additional studies are required to determine whether outcomes following disease-modifying therapies are influenced by SES. © 2016 John Wiley & Sons Ltd.

Plasma lipidomics reveals potential prognostic signatures within a cohort of cystic fibrosis patients

PubMed Central

Ollero, Mario; Astarita, Giuseppe; Guerrera, Ida Chiara; Sermet-Gaudelus, Isabelle; Trudel, Stéphanie; Piomelli, Daniele; Edelman, Aleksander

2011-01-01

Cystic fibrosis (CF) is associated with abnormal lipid metabolism. We have recently shown variations in plasma levels of several phosphatidylcholine (PC) and lysophopshatidylcholine (LPC) species related to disease severity in CF patients. Here our goal was to search for blood plasma lipid signatures characteristic of CF patients bearing the same mutation (F508del) and different phenotypes, and to study their correlation with forced expiratory volume in 1 s (FEV1) and Pseudomonas aeruginosa chronic infection, evaluated at the time of testing (t = 0) and three years later (t = 3). Samples from 44 F508del homozygotes were subjected to a lipidomic approach based on LC-ESI-MS. Twelve free fatty acids were positively correlated with FEV1 at t = 0 (n = 29). Four of them (C20:3n-9, C20:5n-3, C22:5n-3, and C22:6n-3) were also positively correlated with FEV1 three years later, along with PC(32:2) and PC(36:4) (n = 31). Oleoylethanolamide (OEA) was negatively correlated with FEV1 progression (n = 17). Chronically infected patients at t = 0 showed lower PC(32:2), PC(38:5), and C18:3n-3 and higher cholesterol, cholesterol esters, and triacylglycerols (TAG). Chronically infected patients at t = 3 showed significantly lower levels of LPC(18:0). These results suggest a potential prognostic value for some lipid signatures in, to our knowledge, the first longitudinal study aimed at identifying lipid biomarkers for CF. PMID:21335323

Molecular Pathways: Extracting Medical Knowledge from High Throughput Genomic Data

PubMed Central

Goldstein, Theodore; Paull, Evan O.; Ellis, Matthew J.; Stuart, Joshua M.

2013-01-01

High-throughput genomic data that measures RNA expression, DNA copy number, mutation status and protein levels provide us with insights into the molecular pathway structure of cancer. Genomic lesions (amplifications, deletions, mutations) and epigenetic modifications disrupt biochemical cellular pathways. While the number of possible lesions is vast, different genomic alterations may result in concordant expression and pathway activities, producing common tumor subtypes that share similar phenotypic outcomes. How can these data be translated into medical knowledge that provides prognostic and predictive information? First generation mRNA expression signatures such as Genomic Health's Oncotype DX already provide prognostic information, but do not provide therapeutic guidance beyond the current standard of care – which is often inadequate in high-risk patients. Rather than building molecular signatures based on gene expression levels, evidence is growing that signatures based on higher-level quantities such as from genetic pathways may provide important prognostic and diagnostic cues. We provide examples of how activities for molecular entities can be predicted from pathway analysis and how the composite of all such activities, referred to here as the “activitome,” help connect genomic events to clinical factors in order to predict the drivers of poor outcome. PMID:23430023

Prognostic indicators of poor short-term outcome of physiotherapy intervention in women with stress urinary incontinence.

PubMed

Hendriks, Erik J M; Kessels, Alfons G H; de Vet, Henrica C W; Bernards, Arnold T M; de Bie, Rob A

2010-03-01

To identify prognostic indicators independently associated with poor outcome of physiotherapy intervention in women with primary or recurrent stress urinary incontinence (stress UI). A prospective cohort study was performed in physiotherapy practices in primary care to identify prognostic indicators 12 weeks after initiation of physiotherapy intervention. Patients were referred by general practitioners or urogynecologists. Risk factors for stress UI were examined as potential prognostic indicators of poor outcome. The primary outcomes were defined as poor outcome on the binary Leakage Severity scale (LS scale) and the binary global perceived effectiveness (GPE) score. Two hundred sixty-seven women, with a mean age of 47.7 (SD = 8.3), with stress UI for at least 6 months were included. At 12 weeks, 43% and 59% of the women were considered recovered on the binary LS scale and the binary GPE score, respectively. Prognostic indicators associated with poor outcome included 11 indicators based on the binary LS scale and 8 based on the binary GPE score. The prognostic indicators shared by both models show that poor recovery was associated with women with severe stress UI, POP-Q stage > II, poor outcome of physiotherapy intervention for a previous UI episode, prolonged second stage of labor, BMI > 30, high psychological distress, and poor physical health. This study provides robust evidence of clinically meaningful prognostic indicators of poor short-term outcome. These findings need to be confirmed by replication studies. (c) 2009 Wiley-Liss, Inc.

The expression level of BAALC-associated microRNA miR-3151 is an independent prognostic factor in younger patients with cytogenetic intermediate-risk acute myeloid leukemia

PubMed Central

Díaz-Beyá, M; Brunet, S; Nomdedéu, J; Cordeiro, A; Tormo, M; Escoda, L; Ribera, J M; Arnan, M; Heras, I; Gallardo, D; Bargay, J; Queipo de Llano, M P; Salamero, O; Martí, J M; Sampol, A; Pedro, C; Hoyos, M; Pratcorona, M; Castellano, J J; Nomdedeu, M; Risueño, R M; Sierra, J; Monzó, M; Navarro, A; Esteve, J

2015-01-01

Acute myeloid leukemia (AML) is a heterogeneous disease whose prognosis is mainly related to the biological risk conferred by cytogenetics and molecular profiling. In elderly patients (⩾60 years) with normal karyotype AML miR-3151 have been identified as a prognostic factor. However, miR-3151 prognostic value has not been examined in younger AML patients. In the present work, we have studied miR-3151 alone and in combination with BAALC, its host gene, in a cohort of 181 younger intermediate-risk AML (IR-AML) patients. Patients with higher expression of miR-3151 had shorter overall survival (P=0.0025), shorter leukemia-free survival (P=0.026) and higher cumulative incidence of relapse (P=0.082). Moreover, in the multivariate analysis miR-3151 emerged as independent prognostic marker in both the overall series and within the unfavorable molecular prognostic category. Interestingly, the combined determination of both miR-3151 and BAALC improved this prognostic stratification, with patients with low levels of both parameters showing a better outcome compared with those patients harboring increased levels of one or both markers (P=0.003). In addition, we studied the microRNA expression profile associated with miR-3151 identifying a six-microRNA signature. In conclusion, the analysis of miR-3151 and BAALC expression may well contribute to an improved prognostic stratification of younger patients with IR-AML. PMID:26430723

Profiles of neurological outcome prediction among intensivists.

PubMed

Racine, Eric; Dion, Marie-Josée; Wijman, Christine A C; Illes, Judy; Lansberg, Maarten G

2009-12-01

Advances in intensive care medicine have increased survival rates of patients with critical neurological conditions. The focus of prognostication for such patients is therefore shifting from predicting chances of survival to meaningful neurological recovery. This study assessed the variability in long-term outcome predictions among physicians and aimed to identify factors that may account for this variability. Based on a clinical vignette describing a comatose patient suffering from post-anoxic brain injury intensivists were asked in a semi-structured interview about the patient's specific neurological prognosis and about prognostication in general. Qualitative research methods were used to identify areas of variability in prognostication and to classify physicians according to specific prognostication profiles. Quantitative statistics were used to assess for associations between prognostication profiles and physicians' demographic and practice characteristics. Eighteen intensivists participated. Functional outcome predictions varied along an evaluative dimension (fair/good-poor) and a confidence dimension (certain-uncertain). More experienced physicians tended to be more pessimistic about the patient's functional outcome and more certain of their prognosis. Attitudes toward quality of life varied along an evaluative dimension (good-poor) and a "style" dimension (objective-subjective). Older and more experienced physicians were more likely to express objective judgments of quality of life and to predict a worse quality of life for the patient than their younger and less experienced counterparts. Various prognostication profiles exist among intensivists. These may be dictated by factors such as physicians' age and clinical experience. Awareness of these associations may be a first step to more uniform prognostication.

Clinical features of patients with nodal marginal zone lymphoma compared to follicular lymphoma: similar presentation, but differences in prognostic factors and rate of transformation.

PubMed

van den Brand, Michiel; van der Velden, Walter J F M; Diets, Illja J; Ector, Geneviève I C G; de Haan, Anton F J; Stevens, Wendy B C; Hebeda, Konnie M; Groenen, Patricia J T A; van Krieken, Han J M

2016-07-01

Nodal marginal zone lymphoma (NMZL) is a rare type of B-cell non-Hodgkin lymphoma. This study assessed the clinical features of 56 patients with NMZL in comparison to 46 patients with follicular lymphoma (FL). Patients with NMZL and FL had a largely similar clinical presentation, but patients with FL had a higher disease stage at presentation, more frequent abdominal lymphadenopathy and bone marrow involvement, and showed more common transformation into diffuse large B-cell lymphoma (DLBCL) during the course of disease. Overall survival and event-free survival were similar for patients with NMZL and FL, but factors associated with worse prognosis differed between the two groups. Transformation into DLBCL was associated with a significantly poorer outcome in both groups, but the phenotypes were different: DLBCL arising in FL was mainly of germinal center B-cell phenotype, whereas DLBCL arising in NMZL was mainly of non-germinal center B-cell phenotype.

The changing face of Usher syndrome: clinical implications.

PubMed

Cohen, Mazal; Bitner-Glindzicz, Maria; Luxon, Linda

2007-02-01

Usher syndrome is both genetically and phenotypically heterogeneous. Traditionally, the condition has been classified into three clinical types, differentiated by the severity and progression of the hearing impairment and by the presence or absence of vestibular symptoms. Recent advances in molecular genetics have enabled researchers to study the phenotypic expression in confirmed molecular groups of Usher. In response to the expansion of clinical and genetic information on Usher, we report an up to date review of the different clinical forms of Usher in known molecular groups and use the emerging evidence to appraise the diagnostic utility of the traditional classification of Usher. Our findings undermine the traditional view that the clinical types of Usher have distinct genetic causes. The pleiotropic effects of some of the major causes of Usher lead to considerable overlap between the different clinical types, with very little evidence for phenotypic-genotypic correlations. The novel synthesis emerging from this review suggests more productive approaches to the diagnosis of Usher in hearing-impaired children which would provide more accurate prognostic information to families.

Using prognostic models in CLL to personalize approach to clinical care: Are we there yet?

PubMed

Mina, Alain; Sandoval Sus, Jose; Sleiman, Elsa; Pinilla-Ibarz, Javier; Awan, Farrukh T; Kharfan-Dabaja, Mohamed A

2018-03-01

Four decades ago, two staging systems were developed to help stratify CLL into different prognostic categories. These systems, the Rai and the Binet staging, depended entirely on abnormal exam findings and evidence of anemia and thrombocytopenia. Better understanding of biologic, genetic, and molecular characteristics of CLL have contributed to better appreciating its clinical heterogeneity. New prognostic models, the GCLLSG prognostic index and the CLL-IPI, emerged. They incorporate biologic and genetic information related to CLL and are capable of predicting survival outcomes and cases anticipated to need therapy earlier in the disease course. Accordingly, these newer models are helping develop better informed surveillance strategies and ultimately tailor treatment intensity according to presence (or lack thereof) of certain prognostic markers. This represents a step towards personalizing care of CLL patients. We anticipate that as more prognostic factors continue to be identified, the GCLLSG prognostic index and CLL-IPI models will undergo further revisions. Copyright © 2017 Elsevier Ltd. All rights reserved.

New breast cancer prognostic factors identified by computer-aided image analysis of HE stained histopathology images

PubMed Central

Chen, Jia-Mei; Qu, Ai-Ping; Wang, Lin-Wei; Yuan, Jing-Ping; Yang, Fang; Xiang, Qing-Ming; Maskey, Ninu; Yang, Gui-Fang; Liu, Juan; Li, Yan

2015-01-01

Computer-aided image analysis (CAI) can help objectively quantify morphologic features of hematoxylin-eosin (HE) histopathology images and provide potentially useful prognostic information on breast cancer. We performed a CAI workflow on 1,150 HE images from 230 patients with invasive ductal carcinoma (IDC) of the breast. We used a pixel-wise support vector machine classifier for tumor nests (TNs)-stroma segmentation, and a marker-controlled watershed algorithm for nuclei segmentation. 730 morphologic parameters were extracted after segmentation, and 12 parameters identified by Kaplan-Meier analysis were significantly associated with 8-year disease free survival (P < 0.05 for all). Moreover, four image features including TNs feature (HR 1.327, 95%CI [1.001 - 1.759], P = 0.049), TNs cell nuclei feature (HR 0.729, 95%CI [0.537 - 0.989], P = 0.042), TNs cell density (HR 1.625, 95%CI [1.177 - 2.244], P = 0.003), and stromal cell structure feature (HR 1.596, 95%CI [1.142 - 2.229], P = 0.006) were identified by multivariate Cox proportional hazards model to be new independent prognostic factors. The results indicated that CAI can assist the pathologist in extracting prognostic information from HE histopathology images for IDC. The TNs feature, TNs cell nuclei feature, TNs cell density, and stromal cell structure feature could be new prognostic factors. PMID:26022540

Clinicopathologic and prognostic significance of C-reactive protein/albumin ratio in patients with solid tumors: an updated systemic review and meta-analysis.

PubMed

Wu, Jiayuan; Tan, Wenkai; Chen, Lin; Huang, Zhe; Mai, Shao

2018-03-02

C-reactive protein/albumin ratio (CAR) was originally used as a novel inflammation-based prognostic score in predicting outcomes in septic patients. Recently, more and more studies have reported the prognostic value of pretreatment CAR in solid tumors. However, the results remain controversial rather than conclusive. We conducted a meta-analysis based on 24 studies with 10203 patients to explore the relationship between CAR and survival outcomes in patients with solid tumors. The correlation between CAR and clinicopathological parameters was also assessed. Hazard ratio (HR) or odds ratio (OR) with its 95% confidence interval (CI) was applied to be the effect size estimate. The overall results showed that elevated CAR was associated with shorter overall survival (OS) (including 23 studies and 10067 patients) and poorer disease-free survival (DFS) (including 6 studies and 2904 patients). Significant associations between high CAR level and poor OS were also found in the subgroup analyses of study region, cancer type, primary treatment, clinical stage, cut-off selection, sample size, and cut-off value. Moreover, subgroup analyses demonstrated that study region, primary treatment, clinical stage, sample size, and cut-off value did not alter the prognostic value of CAR for DFS. Furthermore, elevated CAR was correlated with certain phenotypes of tumor aggressiveness, such as poor histological grade, serious clinical stage, advanced tumor depth, positive lymph node metastasis, and positive distant metastasis. Together, our meta-analysis suggests that elevated level of serum CAR predicts worse survival and unfavorable clinical characteristics in cancer patients, and CAR may serve as an effective prognostic factor for solid tumors.

Rational bases for the use of the Immunoscore in routine clinical settings as a prognostic and predictive biomarker in cancer patients.

PubMed

Kirilovsky, Amos; Marliot, Florence; El Sissy, Carine; Haicheur, Nacilla; Galon, Jérôme; Pagès, Franck

2016-08-01

The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) tumor, nodes, metastasis (TNM) classification system based on tumor features is used for prognosis estimation and treatment recommendations in most cancers. However, the clinical outcome can vary significantly among patients within the same tumor stage and TNM classification does not predict response to therapy. Therefore, many efforts have been focused on the identification of new markers. Multiple tumor cell-based approaches have been proposed but very few have been translated into the clinic. The recent demonstration of the essential role of the immune system in tumor progression has allowed great advances in the understanding of this complex disease and in the design of novel therapies. The analysis of the immune infiltrate by imaging techniques in large patient cohorts highlighted the prognostic impact of the in situ immune cell infiltrate in tumors. Moreover, the characterization of the immune infiltrates (e.g. type, density, distribution within the tumor, phenotype, activation status) in patients treated with checkpoint-blockade strategies could provide information to predict the disease outcome. In colorectal cancer, we have developed a prognostic score ('Immunoscore') that takes into account the distribution of the density of both CD3(+) lymphocytes and CD8(+) cytotoxic T cells in the tumor core and the invasive margin that could outperform TNM staging. Currently, an international retrospective study is under way to validate the Immunoscore prognostic performance in patients with colon cancer. The use of Immunoscore in clinical practice could improve the patients' prognostic assessment and therapeutic management. © The Japanese Society for Immunology. 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A novel literature-based approach to identify genetic and molecular predictors of survival in glioblastoma multiforme: Analysis of 14,678 patients using systematic review and meta-analytical tools.

PubMed

Thuy, Matthew N T; Kam, Jeremy K T; Lee, Geoffrey C Y; Tao, Peter L; Ling, Dorothy Q; Cheng, Melissa; Goh, Su Kah; Papachristos, Alexander J; Shukla, Lipi; Wall, Krystal-Leigh; Smoll, Nicolas R; Jones, Jordan J; Gikenye, Njeri; Soh, Bob; Moffat, Brad; Johnson, Nick; Drummond, Katharine J

2015-05-01

Glioblastoma multiforme (GBM) has a poor prognosis despite maximal multimodal therapy. Biomarkers of relevance to prognosis which may also identify treatment targets are needed. A few hundred genetic and molecular predictors have been implicated in the literature, however with the exception of IDH1 and O6-MGMT, there is uncertainty regarding their true prognostic relevance. This study analyses reported genetic and molecular predictors of prognosis in GBM. For each, its relationship with univariate overall survival in adults with GBM is described. A systematic search of MEDLINE (1998-July 2010) was performed. Eligible papers studied the effect of any genetic or molecular marker on univariate overall survival in adult patients with histologically diagnosed GBM. Primary outcomes were median survival difference in months and univariate hazard ratios. Analyses included converting 126 Kaplan-Meier curves and 27 raw data sets into primary outcomes. Seventy-four random effects meta-analyses were performed on 39 unique genetic or molecular factors. Objective criteria were designed to classify factors into the categories of clearly prognostic, weakly prognostic, non-prognostic and promising. Included were 304 publications and 174 studies involving 14,678 unique patients from 33 countries. We identified 422 reported genetic and molecular predictors, of which 52 had ⩾2 studies. IDH1 mutation and O6-MGMT were classified as clearly prognostic, validating the methodology. High Ki-67/MIB-1 and loss of heterozygosity of chromosome 10/10q were classified as weakly prognostic. Four factors were classified as non-prognostic and 13 factors were classified as promising and worthy of additional investigation. Funnel plot analysis did not identify any evidence of publication bias. This study demonstrates a novel literature and meta-analytical based approach to maximise the value that can be derived from the plethora of literature reports of molecular and genetic factors in GBM. Caution is advised in over-interpreting the results due to study limitations. Further research to develop this methodology and improvements in study reporting are suggested. Copyright © 2014 Elsevier Ltd. All rights reserved.

Integrated analysis of DNA methylation, immunohistochemistry and mRNA expression, data identifies a Methylation Expression Index (MEI) robustly associated with survival of ER-positive breast cancer patients

PubMed Central

Garcia-Closas, Montserrat; Davis, Sean; Meltzer, Paul; Lissowska, Jolanta; Horne, Hisani N.; Sherman, Mark E.; Lee, Maxwell

2015-01-01

Identification of prognostic gene expression signatures may enable improved decisions about management of breast cancer. To identify a prognostic signature for breast cancer, we performed DNA methylation profiling and identified methylation markers that were associated with expression of ER, PR, HER2, CK5/6 and EGFR proteins. Methylation markers that were correlated with corresponding mRNA expression levels were identified using 208 invasive tumors from a population-based case-control study conducted in Poland. Using this approach, we defined the Methylation Expression Index (MEI) signature that was based on a weighted sum of mRNA levels of 57 genes. Classification of cases as low or high MEI scores were related to survival using Cox regression models. In the Polish study, women with ER-positive low MEI cancers had reduced survival at a median of 5.20 years of follow-up, HR=2.85 95%CI=1.25-6.47. Low MEI was also related to decreased survival in four independent datasets totaling over 2500 ER-positive breast cancers. These results suggest that integrated analysis of tumor expression markers, DNA methylation, and mRNA data can be an important approach for identifying breast cancer prognostic signatures. Prospective assessment of MEI along with other prognostic signatures should be evaluated in future studies. PMID:25773928

Computational analysis identifies putative prognostic biomarkers of pathological scarring in skin wounds.

PubMed

Nagaraja, Sridevi; Chen, Lin; DiPietro, Luisa A; Reifman, Jaques; Mitrophanov, Alexander Y

2018-02-20

Pathological scarring in wounds is a prevalent clinical outcome with limited prognostic options. The objective of this study was to investigate whether cellular signaling proteins could be used as prognostic biomarkers of pathological scarring in traumatic skin wounds. We used our previously developed and validated computational model of injury-initiated wound healing to simulate the time courses for platelets, 6 cell types, and 21 proteins involved in the inflammatory and proliferative phases of wound healing. Next, we analysed thousands of simulated wound-healing scenarios to identify those that resulted in pathological (i.e., excessive) scarring. Then, we identified candidate proteins that were elevated (or decreased) at the early stages of wound healing in those simulations and could therefore serve as predictive biomarkers of pathological scarring outcomes. Finally, we performed logistic regression analysis and calculated the area under the receiver operating characteristic curve to quantitatively assess the predictive accuracy of the model-identified putative biomarkers. We identified three proteins (interleukin-10, tissue inhibitor of matrix metalloproteinase-1, and fibronectin) whose levels were elevated in pathological scars as early as 2 weeks post-wounding and could predict a pathological scarring outcome occurring 40 days after wounding with 80% accuracy. Our method for predicting putative prognostic wound-outcome biomarkers may serve as an effective means to guide the identification of proteins predictive of pathological scarring.

Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer

PubMed Central

Shigeyasu, Kunitoshi; Nagasaka, Takeshi; Mori, Yoshiko; Yokomichi, Naosuke; Kawai, Takashi; Fuji, Tomokazu; Kimura, Keisuke; Umeda, Yuzo; Kagawa, Shunsuke; Goel, Ajay; Fujiwara, Toshiyoshi

2015-01-01

Background To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown. Methods This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox’s proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1 methylation status in relation to overall survival (OS). Results By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088), better tumor differentiation (P = 0.0267) and CIMP-high and MLH1 3' methylated status (P = 0.0312). Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis. Conclusions CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer. PMID:26121593

Predictive value of CpG island methylator phenotype for tumor recurrence in hepatitis B virus-associated hepatocellular carcinoma following liver transplantation

PubMed Central

2010-01-01

Background CpG island methylator phenotype (CIMP), in which multiple genes concordantly methylated, has been demonstrated to be associated with progression, recurrence, as well as overall survival in some types of cancer. Methods We examined the promoter methylation status of seven genes including P16, CDH1, GSTP1, DAPK, XAF1, SOCS1 and SYK in 65 cases of HCC treated with LT by methylation-specific PCR. CIMP+ was defined as having three or more genes that are concordantly methylated. The relationship between CIMP status and clinicopathological parameters, as well as tumor recurrence was further analyzed. Results CIMP+ was more frequent in HCC with AFP > 400 ng/ml than those with AFP ≤ 400 ng/ml (P = 0.017). In addition, patients with CIMP+ were prone to have multiple tumor numbers than those with CIMP- (P = 0.007). Patients with CIMP+ tumors had significantly worse recurrence-free survival (RFS) than patients with CIMP-tumors by Kaplan-Meier estimates (P = 0.004). Multivariate analysis also revealed that CIMP status might be a novel independent prognostic factor of RFS for HCC patients treated with LT (HR: 3.581; 95% CI: 1.473-8.710, P = 0.005). Conclusion Our results suggested that CIMP could serve as a new prognostic biomarker to predict the risk of tumor recurrence in HCC after transplantation. PMID:20678188

Serum-circulating miRNAs predict neuroblastoma progression in mouse model of high-risk metastatic disease.

PubMed

Ramraj, Satish Kumar; Aravindan, Sheeja; Somasundaram, Dinesh Babu; Herman, Terence S; Natarajan, Mohan; Aravindan, Natarajan

2016-04-05

Circulating miRNAs have momentous clinical relevance as prognostic biomarkers and in the progression of solid tumors. Recognizing novel candidates of neuroblastoma-specific circulating miRNAs would allow us to identify potential prognostic biomarkers that could predict the switch from favorable to high-risk metastatic neuroblastoma (HR-NB). Utilizing mouse models of favorable and HR-NB and whole miRnome profiling, we identified high serum levels of 34 and low levels of 46 miRNAs in animals with HR-NB. Preferential sequence homology exclusion of mouse miRNAs identified 25 (11 increased; 14 decreased) human-specific prognostic marker candidates, of which, 21 were unique to HR-NB. miRNA QPCR validated miRnome profile. Target analysis defined the candidate miRNAs' signal transduction flow-through and demonstrated their converged roles in tumor progression. miRNA silencing studies verified the function of select miRNAs on the translation of at least 14 target proteins. Expressions of critical targets that correlate tumor progression in tissue of multifarious organs identify the orchestration of HR-NB. Significant (>10 fold) increase in serum levels of miR-381, miR-548h, and miR-580 identify them as potential prognostic markers for neuroblastoma progression. For the first time, we identified serum-circulating miRNAs that predict the switch from favorable to HR-NB and, further imply that these miRNAs could play a functional role in tumor progression.

PHF21B overexpression promotes cancer stem cell-like traits in prostate cancer cells by activating the Wnt/β-catenin signaling pathway.

PubMed

Li, Qiji; Ye, Liping; Guo, Wei; Wang, Min; Huang, Shuai; Peng, Xinsheng

2017-06-23

PHF21B is newly identified to be involved in the tumor progression; however, its biological role and molecular mechanism in prostate cancer have not been defined. This study is aimed to study the role of PHF21B in the progression of prostate cancer. Real-time PCR, immunohistochemistry and western blotting analysis were used to determine PHF21B expression in prostate cancer cell lines and clinical specimens. The role of PHF21B in maintaining prostate cancer stem cell-like phenotype was examined by tumor-sphere formation assay and expression levels of stem cell markers. Luciferase reporter assay, western blot analysis, enzyme-linked immunosorbent assay and ChIP assay were used to determine whether PHF21B activates the Wnt/β-catenin signaling by transcriptionally downregulating SFRP1 and SFRP2. Our results revealed that PHF21B was markedly upregulated in prostate cancer cell lines and tissues. High PHF21B levels predicted poorer recurrence-free survival in prostate cancer patients. Gain-of-function and loss-of-function studies showed that overexpression of PHF21B enhanced, while downregulation suppressed, the cancer stem cell-like phenotype in prostate cancer cells. Xenograft tumor model showed that silencing PHF21B decreased the ability of tumorigenicity in vivo. Notably, Wnt/β-catenin signaling was hyperactivated in prostate cancer cells overexpressing PHF21B, and mediated PHF21B-induced cancer stem cell-like phenotype. Furthermore, PHF21B suppressed repressors of the Wnt/β-catenin signaling cascade, including SFRP1 and SFRP2. These results demonstrated that PHF21B constitutively activated wnt/β-catenin signaling by transcriptionally downregulating SFRP1 and SFRP2, which promotes prostate cancer stem cell-like phenotype. Our results revealed that PHF21B functions as an oncogene in prostate cancer, and may represent a promising prognostic biomarker and an attractive candidate for target therapy of prostate cancer.

Old, New, and Emerging Immunohistochemical Markers in Pheochromocytoma and Paraganglioma.

PubMed

Cheung, Veronica K Y; Gill, Anthony J; Chou, Angela

2018-05-19

The evolution of genetic research over the past two decades has greatly improved the understanding of pheochromocytomas and paragangliomas. It is now accepted that more than one third of pheochromocytoma and paragangliomas arise in the context of syndromic disease, usually hereditary. The genetic profile of these tumors also has important prognostic implications which may help guide treatment. Accompanying the changing molecular landscape is the development of new immunohistochemical markers. Initially used in assisting with diagnosis, immunohistochemical markers have now become an important adjunct to screening programs for inherited conditions and subsequently as prognostic markers. The accessibility and efficiency of immunohistochemistry bring pathologists to the forefront in triaging patients based on tumor genotype-phenotype. In this review, we provide an update on the role of immunohistochemistry in the diagnosis of pheochromocytomas and paragangliomas, as an adjunct to assessment for hereditary disease and finally as a potential tool to assist risk stratification.

Survival rate and prognostic factors of conventional osteosarcoma in Northern Thailand: A series from Chiang Mai University Hospital.

PubMed

Pruksakorn, Dumnoensun; Phanphaisarn, Areerak; Arpornchayanon, Olarn; Uttamo, Nantawat; Leerapun, Taninnit; Settakorn, Jongkolnee

2015-12-01

Osteosarcoma is a common and aggressive primary malignant bone tumor occurring in children and adolescents. It is one of the most aggressive human cancers and the most common cause of cancer-associated limb loss. As treatment in Thailand has produced a lower survival rate than in developed countries; therefore, this study identified survival rate and the poor prognostic factors of osteosarcoma in Northern Thailand. The retrospective cases of osteosarcoma, diagnosis between 1 January 1996 and 31 December 2013, were evaluated. Five and ten year overall survival rates were analyzed using time-to-event analysis. Potential prognostic factors were identified by multivariate regression analysis. There were 208 newly diagnosed osteosarcomas during that period, and 144 cases met the criteria for analysis. The majority of the osteosarcoma cases (78.5%) were aged 0-24 years. The overall 5- and 10-year survival rates were 37.9% and 33.6%, respectively. Presence of metastasis at initial examination, delayed and against treatment co-operation, and axial skeletal location were identified as independent prognostic factors for survival, with hazard ratios of 4.3, 2.5 and 3.8, and 3.1, respectively. This osteosarcoma cohort had a relatively poor overall survival rate. The prognostic factors identified would play a critical role in modifying survival rates of osteosarcoma patients; as rapid disease recognition, a better treatment counselling, as well as improving of chemotherapeutic regimens were found to be important in improving the overall survival rate in Thailand. Copyright © 2015 Elsevier Ltd. All rights reserved.

Incidence and prognostic factors for postoperative frozen shoulder after shoulder surgery: a prospective cohort study.

PubMed

Koorevaar, Rinco C T; Van't Riet, Esther; Ipskamp, Marcel; Bulstra, Sjoerd K

2017-03-01

Frozen shoulder is a potential complication after shoulder surgery. It is a clinical condition that is often associated with marked disability and can have a profound effect on the patient's quality of life. The incidence, etiology, pathology and prognostic factors of postoperative frozen shoulder after shoulder surgery are not known. The purpose of this explorative study was to determine the incidence of postoperative frozen shoulder after various operative shoulder procedures. A second aim was to identify prognostic factors for postoperative frozen shoulder after shoulder surgery. 505 consecutive patients undergoing elective shoulder surgery were included in this prospective cohort study. Follow-up was 6 months after surgery. A prediction model was developed to identify prognostic factors for postoperative frozen shoulder after shoulder surgery using the TRIPOD guidelines. We nominated five potential predictors: gender, diabetes mellitus, type of physiotherapy, arthroscopic surgery and DASH score. Frozen shoulder was identified in 11% of the patients after shoulder surgery and was more common in females (15%) than in males (8%). Frozen shoulder was encountered after all types of operative procedures. A prediction model based on four variables (diabetes mellitus, specialized shoulder physiotherapy, arthroscopic surgery and DASH score) discriminated reasonably well with an AUC of 0.712. Postoperative frozen shoulder is a serious complication after shoulder surgery, with an incidence of 11%. Four prognostic factors were identified for postoperative frozen shoulder: diabetes mellitus, arthroscopic surgery, specialized shoulder physiotherapy and DASH score. The combination of these four variables provided a prediction rule for postoperative frozen shoulder with reasonable fit. Level II, prospective cohort study.

Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones

PubMed Central

Plevova, Karla; Francova, Hana Skuhrova; Burckova, Katerina; Brychtova, Yvona; Doubek, Michael; Pavlova, Sarka; Malcikova, Jitka; Mayer, Jiri; Tichy, Boris; Pospisilova, Sarka

2014-01-01

In chronic lymphocytic leukemia, usually a monoclonal disease, multiple productive immunoglobulin heavy chain gene rearrangements are identified sporadically. Prognostication of such cases based on immunoglobulin heavy variable gene mutational status can be problematic, especially if the different rearrangements have discordant mutational status. To gain insight into the possible biological mechanisms underlying the origin of the multiple rearrangements, we performed a comprehensive immunogenetic and immunophenotypic characterization of 31 cases with the multiple rearrangements identified in a cohort of 1147 patients with chronic lymphocytic leukemia. For the majority of cases (25/31), we provide evidence of the co-existence of at least two B lymphocyte clones with a chronic lymphocytic leukemia phenotype. We also identified clonal drifts in serial samples, likely driven by selection forces. More specifically, higher immunoglobulin variable gene identity to germline and longer complementarity determining region 3 were preferred in persistent or newly appearing clones, a phenomenon more pronounced in patients with stereotyped B-cell receptors. Finally, we report that other factors, such as TP53 gene defects and therapy administration, influence clonal selection. Our findings are relevant to clonal evolution in the context of antigen stimulation and transition of monoclonal B-cell lymphocytosis to chronic lymphocytic leukemia. PMID:24038023

Poor CMV-specific CD8+ T central memory subset recovery at early stage post-HSCT associates with refractory and recurrent CMV reactivation.

PubMed

Liu, Jing; Chang, Ying-Jun; Yan, Chen-Hua; Xu, Lan-Ping; Jiang, Zheng-Fan; Zhang, Xiao-Hui; Liu, Kai-Yan; Huang, Xiao-Jun

2016-09-01

Refractory and recurrent cytomegalovirus (CMV) reactivation were independent risk factors of CMV disease and transplant-related mortality post allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our aims were to identify the recovery of CMV-specific CD8+ T cells with a central memory phenotype (TCM) associated with refractory and recurrent CMV reactivation. We analyzed findings in a prospective study comprising (n = 107) post allo-HSCT. CMV-specific CD8+ T cells were determined using HLA class I pentamers together with extended phenotypic analyses. The patients with lower level of CMV-specific CD8+ TCM at day 30 post-HSCT had an increased risk of refractory and recurrent CMV (68.5%) comparing with the higher one (13.2%) (p < 0.001) and poorer long term CMV-specific CD8+ T cell reconstitution post-HSCT (p = 0.026). Multivariate analysis revealed that CMV-specific CD8+ TCM at day 30 was an independent prognostic factor for refractory and recurrent reactivation (p = 0.002). The CMV-specific CD8+ TCM subset at day 30 post-HSCT is associated with CMV-specific T cell immunity recovery as well as the refractory and recurrent CMV reactivation post-HSCT. Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Prognostic models for predicting posttraumatic seizures during acute hospitalization, and at 1 and 2 years following traumatic brain injury.

PubMed

Ritter, Anne C; Wagner, Amy K; Szaflarski, Jerzy P; Brooks, Maria M; Zafonte, Ross D; Pugh, Mary Jo V; Fabio, Anthony; Hammond, Flora M; Dreer, Laura E; Bushnik, Tamara; Walker, William C; Brown, Allen W; Johnson-Greene, Doug; Shea, Timothy; Krellman, Jason W; Rosenthal, Joseph A

2016-09-01

Posttraumatic seizures (PTS) are well-recognized acute and chronic complications of traumatic brain injury (TBI). Risk factors have been identified, but considerable variability in who develops PTS remains. Existing PTS prognostic models are not widely adopted for clinical use and do not reflect current trends in injury, diagnosis, or care. We aimed to develop and internally validate preliminary prognostic regression models to predict PTS during acute care hospitalization, and at year 1 and year 2 postinjury. Prognostic models predicting PTS during acute care hospitalization and year 1 and year 2 post-injury were developed using a recent (2011-2014) cohort from the TBI Model Systems National Database. Potential PTS predictors were selected based on previous literature and biologic plausibility. Bivariable logistic regression identified variables with a p-value < 0.20 that were used to fit initial prognostic models. Multivariable logistic regression modeling with backward-stepwise elimination was used to determine reduced prognostic models and to internally validate using 1,000 bootstrap samples. Fit statistics were calculated, correcting for overfitting (optimism). The prognostic models identified sex, craniotomy, contusion load, and pre-injury limitation in learning/remembering/concentrating as significant PTS predictors during acute hospitalization. Significant predictors of PTS at year 1 were subdural hematoma (SDH), contusion load, craniotomy, craniectomy, seizure during acute hospitalization, duration of posttraumatic amnesia, preinjury mental health treatment/psychiatric hospitalization, and preinjury incarceration. Year 2 significant predictors were similar to those of year 1: SDH, intraparenchymal fragment, craniotomy, craniectomy, seizure during acute hospitalization, and preinjury incarceration. Corrected concordance (C) statistics were 0.599, 0.747, and 0.716 for acute hospitalization, year 1, and year 2 models, respectively. The prognostic model for PTS during acute hospitalization did not discriminate well. Year 1 and year 2 models showed fair to good predictive validity for PTS. Cranial surgery, although medically necessary, requires ongoing research regarding potential benefits of increased monitoring for signs of epileptogenesis, PTS prophylaxis, and/or rehabilitation/social support. Future studies should externally validate models and determine clinical utility. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Factors Affecting Physicians' Intentions to Communicate Personalized Prognostic Information to Cancer Patients at the End of Life: An Experimental Vignette Study.

PubMed

Han, Paul K J; Dieckmann, Nathan F; Holt, Christina; Gutheil, Caitlin; Peters, Ellen

2016-08-01

To explore the effects of personalized prognostic information on physicians' intentions to communicate prognosis to cancer patients at the end of life, and to identify factors that moderate these effects. A factorial experiment was conducted in which 93 family medicine physicians were presented with a hypothetical vignette depicting an end-stage gastric cancer patient seeking prognostic information. Physicians' intentions to communicate prognosis were assessed before and after provision of personalized prognostic information, while emotional distress of the patient and ambiguity (imprecision) of the prognostic estimate were varied between subjects. General linear models were used to test the effects of personalized prognostic information, patient distress, and ambiguity on prognostic communication intentions, and potential moderating effects of 1) perceived patient distress, 2) perceived credibility of prognostic models, 3) physician numeracy (objective and subjective), and 4) physician aversion to risk and ambiguity. Provision of personalized prognostic information increased prognostic communication intentions (P < 0.001, η(2) = 0.38), although experimentally manipulated patient distress and prognostic ambiguity had no effects. Greater change in communication intentions was positively associated with higher perceived credibility of prognostic models (P = 0.007, η(2) = 0.10), higher objective numeracy (P = 0.01, η(2) = 0.09), female sex (P = 0.01, η(2) = 0.08), and lower perceived patient distress (P = 0.02, η(2) = 0.07). Intentions to communicate available personalized prognostic information were positively associated with higher perceived credibility of prognostic models (P = 0.02, η(2) = 0.09), higher subjective numeracy (P = 0.02, η(2) = 0.08), and lower ambiguity aversion (P = 0.06, η(2) = 0.04). Provision of personalized prognostic information increases physicians' prognostic communication intentions to a hypothetical end-stage cancer patient, and situational and physician characteristics moderate this effect. More research is needed to confirm these findings and elucidate the determinants of prognostic communication at the end of life. © The Author(s) 2016.

[Prognostic differences of phenotypes in pT1-2N0 invasive breast cancer: a large cohort study with cluster analysis].

PubMed

Wang, Z; Wang, W H; Wang, S L; Jin, J; Song, Y W; Liu, Y P; Ren, H; Fang, H; Tang, Y; Chen, B; Qi, S N; Lu, N N; Li, N; Tang, Y; Liu, X F; Yu, Z H; Li, Y X

2016-06-23

To find phenotypic subgroups of patients with pT1-2N0 invasive breast cancer by means of cluster analysis and estimate the prognosis and clinicopathological features of these subgroups. From 1999 to 2013, 4979 patients with pT1-2N0 invasive breast cancer were recruited for hierarchical clustering analysis. Age (≤40, 41-70, 70+ years), size of primary tumor, pathological type, grade of differentiation, microvascular invasion, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) were chosen as distance metric between patients. Hierarchical cluster analysis was performed using Ward's method. Cophenetic correlation coefficient (CPCC) and Spearman correlation coefficient were used to validate clustering structures. The CPCC was 0.603. The Spearman correlation coefficient was 0.617 (P<0.001), which indicated a good fit of hierarchy to the data. A twelve-cluster model seemed to best illustrate our patient cohort. Patients in cluster 5, 9 and 12 had best prognosis and were characterized by age >40 years, smaller primary tumor, lower histologic grade, positive ER and PR status, and mainly negative HER-2. Patients in the cluster 1 and 11 had the worst prognosis, The cluster 1 was characterized by a larger tumor, higher grade and negative ER and PR status, while the cluster 11 was characterized by positive microvascular invasion. Patients in other 7 clusters had a moderate prognosis, and patients in each cluster had distinctive clinicopathological features and recurrent patterns. This study identified distinctive clinicopathologic phenotypes in a large cohort of patients with pT1-2N0 breast cancer through hierarchical clustering and revealed different prognosis. This integrative model may help physicians to make more personalized decisions regarding adjuvant therapy.

Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene.

PubMed

Charron, P; Dubourg, O; Desnos, M; Bennaceur, M; Carrier, L; Camproux, A C; Isnard, R; Hagege, A; Langlard, J M; Bonne, G; Richard, P; Hainque, B; Bouhour, J B; Schwartz, K; Komajda, M

1998-06-09

Little information is available on phenotype-genotype correlations in familial hypertrophic cardiomyopathy that are related to the cardiac myosin binding protein C (MYBPC3) gene. The aim of this study was to perform this type of analysis. We studied 76 genetically affected subjects from nine families with seven recently identified mutations (SASint20, SDSint7, SDSint23, branch point int23, Glu542Gln, a deletion in exon 25, and a duplication/deletion in exon 33) in the MYBPC3 gene. Detailed clinical, ECG, and echocardiographic parameters were analyzed. An intergene analysis was performed by comparing the MYBPC3 group to seven mutations in the beta-myosin heavy-chain gene (beta-MHC) group (n=52). There was no significant phenotypic difference among the different mutations in the MYBPC3 gene. However, in the MYBPC3 group compared with the beta-MHC group, (1) prognosis was significantly better (P<0.0001), and no deaths occurred before the age of 40 years; (2) the age at onset of symptoms was delayed (41+/-19 versus 35+/-17 years, P<0.002); and (3) before 30 years of age, the phenotype was particularly mild because penetrance was low (41% versus 62%), maximal wall thicknesses lower (12+/-4 versus 16+/-7 mm, P<0.03), and abnormal T waves less frequent (9% versus 45%, P<0.02). These results are consistent with specific clinical features related to the MYBPC3 gene: onset of the disease appears delayed and the prognosis is better than that associated with the beta-MHC gene. These findings could be particularly important for the purpose of clinical management and genetic counseling in familial hypertrophic cardiomyopathy.

Oncologic Phenotype of Peripheral Neuroblastic Tumors Associated With PHOX2B Non-Polyalanine Repeat Expansion Mutations.

PubMed

Heide, Solveig; Masliah-Planchon, Julien; Isidor, Bertrand; Guimier, Anne; Bodet, Damien; Coze, Carole; Deville, Anne; Thebault, Estelle; Pasquier, Corinne Jeanne; Cassagnau, Elisabeth; Pierron, Gaelle; Clément, Nathalie; Schleiermacher, Gudrun; Amiel, Jeanne; Delattre, Olivier; Peuchmaur, Michel; Bourdeaut, Franck

2016-01-01

Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail. We analyzed prognostic factors, treatment toxicity, and outcome of patients with PNT and PHOX2B NPARM. Thirteen patients were identified, six of whom also had CCHS and/or HSCR, one also had late-onset hypoventilation with hypothalamic dysfunction (LO-CHS/HD), and six had no other neurocristopathy. Four tumours were "poorly differentiated," and nine were differentiated, including five ganglioneuromas, three ganglioneuroblastomas, and one differentiating neuroblastoma, hence illustrating that PHOX2B NPARM are predominantly associated with differentiating tumors. Nevertheless, three patients had stage 4 and one patient had stage 3 disease. Segmental chromosomal alterations, correlating with poor prognosis, were found in all the six tumors analyzed by array-comparative genomic hybridization. One patient died of tumor progression, one is on palliative care, one died of hypoventilation, and 10 patients are still alive, with median follow-up of 5 years. Based on histological phenotype, our series suggests that heterozygous PHOX2B NPARM do not fully preclude ganglion cell differentiation in tumors. However, this tumor predisposition syndrome may also be associated with poorly differentiated tumors with unfavorable genomic profiles and clinically aggressive behaviors. The intrafamilial variability and the unpredictable tumor prognosis should be considered in genetic counseling. © 2015 Wiley Periodicals, Inc.

Mitochondrial DNA content in breast cancer: Impact on in vitro and in vivo phenotype and patient prognosis

PubMed Central

Weerts, Marjolein J.A.; Sieuwerts, Anieta M.; Smid, Marcel; Look, Maxime P.; Foekens, John A.; Sleijfer, Stefan; Martens, John W.M.

2016-01-01

Reduced mitochondrial DNA (mtDNA) content in breast cancer cell lines has been associated with transition towards a mesenchymal phenotype, but its clinical consequences concerning breast cancer dissemination remain unidentified. Here, we aimed to clarify the link between mtDNA content and a mesenchymal phenotype and its relation to prognosis of breast cancer patients. We analyzed mtDNA content in 42 breast cancer cell lines and 207 primary breast tumor specimens using a combination of quantitative PCR and array-based copy number analysis. By associating mtDNA content with expression levels of genes involved in epithelial-to-mesenchymal transition (EMT) and with the intrinsic breast cancer subtypes, we could not identify a relation between low mtDNA content and mesenchymal properties in the breast cancer cell lines or in the primary breast tumors. In addition, we explored the relation between mtDNA content and prognosis in our cohort of primary breast tumor specimens that originated from patients with lymph node-negative disease who did not receive any (neo)adjuvant systemic therapy. When patients were divided based on the tumor quartile levels of mtDNA content, those in the lowest quarter (≤ 350 mtDNA molecules per cell) showed a poorer 10-year distant metastasis-free survival than patients with > 350 mtDNA molecules per cell (HR 0.50 [95% CI 0.29–0.87], P = 0.015). The poor prognosis was independent of established clinicopathological markers (HR 0.54 [95% CI 0.30–0.97], P = 0.038). We conclude that, despite a lack of evidence between mtDNA content and EMT, low mtDNA content might provide meaningful prognostic value for distant metastasis in breast cancer. PMID:27081694

Downregulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer.

PubMed

Li, Wentong; Zhai, Limin; Wang, Hui; Liu, Chuanliang; Zhang, Jinbao; Chen, Weijuan; Wei, Qun

2016-05-10

Therapeutic resistance to trastuzumab caused by dysregulation of long noncoding RNAs (lncRNAs) is a major obstacle to clinical management of HER2-positive breast cancer. To investigate which lncRNAs contribute to trastuzumab resistance, we screened a microarray of lncRNAs involved in the malignant phenotype of trastuzumab-resistant SKBR-3/Tr cells. Expression of the lncRNA GAS5 was decreased in SKBR-3/Tr cells and in breast cancer tissue from trastuzumab-treated patients. Inhibition of GAS5 promoted SKBR-3 cell proliferation, and GAS5 knockdown partially reversed lapatinib-induced inhibition of SKBR-3/Tr cell proliferation. GAS5 suppresses cancer proliferation by acting as a molecular sponge for miR-21, leading to the de-repression of phosphatase and tensin homologs (PTEN), the endogenous target of miR-21. Moreover, mTOR activation associated with reduced GAS5 expression was required to suppress PTEN. This work identifies GAS5 as a novel prognostic marker and candidate drug target for HER2-positive breast cancer.

Ventilatory Dysfunction in Parkinson’s Disease

PubMed Central

Baille, Guillaume; De Jesus, Anna Maria; Perez, Thierry; Devos, David; Dujardin, Kathy; Charley, Christelle Monaca; Defebvre, Luc; Moreau, Caroline

2016-01-01

In contrast to some other neurodegenerative diseases, little is known about ventilatory dysfunction in Parkinson’s disease (PD). To assess the spectrum of ventilation disorders in PD, we searched for and reviewed studies of dyspnea, lung volumes, respiratory muscle function, sleep breathing disorders and the response to hypoxemia in PD. Among the studies, we identified some limitations: (i) small study populations (mainly composed of patients with advanced PD), (ii) the absence of long-term follow-up and (iii) the absence of functional evaluations under “off-drug” conditions. Although there are many reports of abnormal spirometry data in PD (mainly related to impairment of the inspiratory muscles), little is known about hypoventilation in PD. We conclude that ventilatory dysfunction in PD has been poorly studied and little is known about its frequency and clinical relevance. Hence, there is a need to characterize the different phenotypes of ventilation disorders in PD, study their relationships with disease progression and assess their prognostic value. PMID:27314755

Clinical utilization of genomics data produced by the international Pseudomonas aeruginosa consortium

PubMed Central

Freschi, Luca; Jeukens, Julie; Kukavica-Ibrulj, Irena; Boyle, Brian; Dupont, Marie-Josée; Laroche, Jérôme; Larose, Stéphane; Maaroufi, Halim; Fothergill, Joanne L.; Moore, Matthew; Winsor, Geoffrey L.; Aaron, Shawn D.; Barbeau, Jean; Bell, Scott C.; Burns, Jane L.; Camara, Miguel; Cantin, André; Charette, Steve J.; Dewar, Ken; Déziel, Éric; Grimwood, Keith; Hancock, Robert E. W.; Harrison, Joe J.; Heeb, Stephan; Jelsbak, Lars; Jia, Baofeng; Kenna, Dervla T.; Kidd, Timothy J.; Klockgether, Jens; Lam, Joseph S.; Lamont, Iain L.; Lewenza, Shawn; Loman, Nick; Malouin, François; Manos, Jim; McArthur, Andrew G.; McKeown, Josie; Milot, Julie; Naghra, Hardeep; Nguyen, Dao; Pereira, Sheldon K.; Perron, Gabriel G.; Pirnay, Jean-Paul; Rainey, Paul B.; Rousseau, Simon; Santos, Pedro M.; Stephenson, Anne; Taylor, Véronique; Turton, Jane F.; Waglechner, Nicholas; Williams, Paul; Thrane, Sandra W.; Wright, Gerard D.; Brinkman, Fiona S. L.; Tucker, Nicholas P.; Tümmler, Burkhard; Winstanley, Craig; Levesque, Roger C.

2015-01-01

The International Pseudomonas aeruginosa Consortium is sequencing over 1000 genomes and building an analysis pipeline for the study of Pseudomonas genome evolution, antibiotic resistance and virulence genes. Metadata, including genomic and phenotypic data for each isolate of the collection, are available through the International Pseudomonas Consortium Database (http://ipcd.ibis.ulaval.ca/). Here, we present our strategy and the results that emerged from the analysis of the first 389 genomes. With as yet unmatched resolution, our results confirm that P. aeruginosa strains can be divided into three major groups that are further divided into subgroups, some not previously reported in the literature. We also provide the first snapshot of P. aeruginosa strain diversity with respect to antibiotic resistance. Our approach will allow us to draw potential links between environmental strains and those implicated in human and animal infections, understand how patients become infected and how the infection evolves over time as well as identify prognostic markers for better evidence-based decisions on patient care. PMID:26483767

Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection.

PubMed

Beuschlein, Felix; Weigel, Jens; Saeger, Wolfgang; Kroiss, Matthias; Wild, Vanessa; Daffara, Fulvia; Libé, Rosella; Ardito, Arianna; Al Ghuzlan, Abir; Quinkler, Marcus; Oßwald, Andrea; Ronchi, Cristina L; de Krijger, Ronald; Feelders, Richard A; Waldmann, Jens; Willenberg, Holger S; Deutschbein, Timo; Stell, Anthony; Reincke, Martin; Papotti, Mauro; Baudin, Eric; Tissier, Frédérique; Haak, Harm R; Loli, Paola; Terzolo, Massimo; Allolio, Bruno; Müller, Hans-Helge; Fassnacht, Martin

2015-03-01

Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. The aim of this study was to identify markers with prognostic value for patients in this clinical setting. From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10-19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.

Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer

PubMed Central

Cha, Yongjun; Kim, Kyung-Ju; Han, Sae-Won; Rhee, Ye Young; Bae, Jeong Mo; Wen, Xianyu; Cho, Nam-Yun; Lee, Dae-Won; Lee, Kyung-Hun; Kim, Tae-Yong; Oh, Do-Youn; Im, Seock-Ah; Bang, Yung-Jue; Jeong, Seung-Yong; Park, Kyu Joo; Kang, Gyeong Hoon; Kim, Tae-You

2016-01-01

Background: The association between the CpG island methylator phenotype (CIMP) and clinical outcomes in metastatic colorectal cancer remains unclear. We investigated the prognostic impact of CIMP in patients with metastatic colorectal cancer treated with systemic chemotherapy. Methods: Eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, CDKN2A, CRABP1, and MLH1) were examined. The CIMP status was determined by the number of methylated promoters as high (⩾5), low (1–4), and negative (0). Results: A total of 153 patients were included (men/women, 103/50; median age, 61 years; range, 22–80 years). The CIMP status was negative/low/high in 77/ 69/7 patients, respectively. Overall survival (OS) was significantly different among the three CIMP groups, with median values of 35.7, 22.2, and 9.77 months for the negative, low, and high groups, respectively (P<0.001). For patients treated with fluoropyrimidine and oxaliplatin first-line chemotherapy (N=128), OS and progression-free survival (PFS) were significantly different among the three CIMP groups; the median OS was 37.9, 23.8, and 6.77 months for the negative, low, and high groups, respectively (P<0.001), while the median PFS was 9.97, 7.87, and 1.83 months, respectively (P=0.002). Response rates were marginally different among the three CIMP groups (53.4% vs 45.1% vs 16.7%, respectively; P=0.107). For patients treated with fluoropyrimidine and irinotecan second-line chemotherapy (N=86), only OS showed a difference according to the CIMP status, with median values of 20.4, 13.4, and 2.90 months for the negative, low, and high groups, respectively (P<0.001). Conclusions: The CIMP status is a negative prognostic factor for patients with metastatic colorectal cancer treated with chemotherapy. PMID:27310704

Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer.

PubMed

Cha, Yongjun; Kim, Kyung-Ju; Han, Sae-Won; Rhee, Ye Young; Bae, Jeong Mo; Wen, Xianyu; Cho, Nam-Yun; Lee, Dae-Won; Lee, Kyung-Hun; Kim, Tae-Yong; Oh, Do-Youn; Im, Seock-Ah; Bang, Yung-Jue; Jeong, Seung-Yong; Park, Kyu Joo; Kang, Gyeong Hoon; Kim, Tae-You

2016-07-12

The association between the CpG island methylator phenotype (CIMP) and clinical outcomes in metastatic colorectal cancer remains unclear. We investigated the prognostic impact of CIMP in patients with metastatic colorectal cancer treated with systemic chemotherapy. Eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, CDKN2A, CRABP1, and MLH1) were examined. The CIMP status was determined by the number of methylated promoters as high (⩾5), low (1-4), and negative (0). A total of 153 patients were included (men/women, 103/50; median age, 61 years; range, 22-80 years). The CIMP status was negative/low/high in 77/ 69/7 patients, respectively. Overall survival (OS) was significantly different among the three CIMP groups, with median values of 35.7, 22.2, and 9.77 months for the negative, low, and high groups, respectively (P<0.001). For patients treated with fluoropyrimidine and oxaliplatin first-line chemotherapy (N=128), OS and progression-free survival (PFS) were significantly different among the three CIMP groups; the median OS was 37.9, 23.8, and 6.77 months for the negative, low, and high groups, respectively (P<0.001), while the median PFS was 9.97, 7.87, and 1.83 months, respectively (P=0.002). Response rates were marginally different among the three CIMP groups (53.4% vs 45.1% vs 16.7%, respectively; P=0.107). For patients treated with fluoropyrimidine and irinotecan second-line chemotherapy (N=86), only OS showed a difference according to the CIMP status, with median values of 20.4, 13.4, and 2.90 months for the negative, low, and high groups, respectively (P<0.001). The CIMP status is a negative prognostic factor for patients with metastatic colorectal cancer treated with chemotherapy.

Prognostic factors for risk stratification of adult cancer patients with chemotherapy-induced febrile neutropenia: a systematic review and meta-analysis.

PubMed

Lee, Yee Mei; Lang, Dora; Lockwood, Craig

Increasing numbers of studies identify new prognostic factors for categorising chemotherapy-induced febrile neutropenia adult cancer patients into high- or low-risk groups for adverse outcomes. These groupings are used to tailor therapy according to level of risk. However many emerging factors with prognostic significance remain controversial, being based on single studies only. A systematic review was conducted to determine the strength of association of all identified factors associated with the outcomes of chemotherapy-induced febrile neutropenia patients. The participants included were adults of 15 years old and above, with a cancer diagnosis and who underwent cancer treatment.The review focused on clinical factors and their association with the outcomes of cancer patients with chemotherapy-induced febrile neutropenia at presentation of fever.All quantitative studies published in English which investigated clinical factors for risk stratification of adult cancer patients with chemotherapy-induced febrile neutropenia were considered.The primary outcome of interest was to identify the clinical factors for risk stratification of adult cancer patients with chemotherapy-induced febrile neutropenia. Electronic databases searched from their respective inception date up to December 2011 include MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Science-Direct, Scopus and Mednar. The quality of the included studies was subjected to assessment by two independent reviewers. The standardised critical appraisal tool from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) was used to assess the following criteria: representativeness of study population; clearly defined prognostic factors and outcomes; whether potential confounders were addressed and appropriate statistical analysis was undertaken for the study design. Data extraction was performed using a modified version of the standardised extraction tool from the JBI-MAStARI. Prognostic factors and the accompanying odds ratio reported for the significance of these factors that were identified by multivariate regression, were extracted from each included study. Studies results were pooled in statistical meta-analysis using Review Manager 5.1. Where statistical pooling was not possible, the findings were presented in narrative form. Seven studies (four prospective cohort and three retrospective cohort) investigating 22 factors in total were included. Fixed effects meta-analysis showed: hypotension [OR=1.66, 95%CI, 1.14-2.41, p=0.008] and thrombocytopenia [OR=3.92, 95%CI, 2.19-7.01, p<0.00001)] were associated with high-risk of adverse outcomes for febrile neutropenia. Other factors that were statistically significant from single studies included: age of patients, clinical presentation at fever onset, presence or absence of co-morbidities, infections, duration and severity of neutropenia state. Five prognostic factors failed to demonstrate an association between the variables and the outcomes measured and they include: presence of pneumonia, total febrile days, median days to fever, recovery from neutropenia and presence of moderate clinical symptoms in association with Gram-negative bacteraemia. Despite the overall limitations identified in the included studies, this review has provided a synthesis of the best available evidence for the prognostic factors used in risk stratification of febrile neutropenia patients. However, the dynamic aspects of prognostic model development, validation and utilisation have not been addressed adequately thus far. Given the findings of this review, it is timely to address these issues and improve the utilisation of prognostic models in the management of febrile neutropenia patients. The identified factors are similar to the factors in current prognostic models. However, additional factors that were reported to be statistically significant in this review (thrombocytopenia, presence of central venous catheter, and duration and severity of neutropenia) have not previously been included in prognostic models. This review has found these factors may improve the performance of current models by adding or replacing some of the factors. The role of risk stratification of chemotherapy-induced febrile neutropenia patients continues to evolve as the practice of risk-based therapy has been demonstrated to be beneficial to patients, clinicians and health care organisations. Further research to identify new factors /markers is needed to develop a new model which is reliable and accurate for these patients, regardless of cancer types. A robust and well-validated prognostic model is the key to enhance patient safety in the risk-based management of cancer patients with chemotherapy-induced febrile neutropenia.

Assessment of published models and prognostic variables in epithelial ovarian cancer at Mayo Clinic

PubMed Central

Hendrickson, Andrea Wahner; Hawthorne, Kieran M.; Goode, Ellen L.; Kalli, Kimberly R.; Goergen, Krista M.; Bakkum-Gamez, Jamie N.; Cliby, William A.; Keeney, Gary L.; Visscher, Dan W.; Tarabishy, Yaman; Oberg, Ann L.; Hartmann, Lynn C.; Maurer, Matthew J.

2015-01-01

Objectives Epithelial ovarian cancer (EOC) is an aggressive disease in which first line therapy consists of a surgical staging/debulking procedure and platinum based chemotherapy. There is significant interest in clinically applicable, easy to use prognostic tools to estimate risk of recurrence and overall survival. In this study we used a large prospectively collected cohort of women with EOC to validate currently published models and assess prognostic variables. Methods Women with invasive ovarian, peritoneal, or fallopian tube cancer diagnosed between 2000-2011 and prospectively enrolled into the Mayo Clinic Ovarian Cancer registry were identified. Demographics and known prognostic markers as well as epidemiologic exposure variables were abstracted from the medical record and collected via questionnaire. Six previously published models of overall and recurrence-free survival were assessed for external validity. In addition, predictors of outcome were assessed in our dataset. Results Previously published models validated with a range of c-statistics (0.587-0.827), though application of models containing variables not part of routine practice were somewhat limited by missing data; utilization of all applicable models and comparison of results is suggested. Examination of prognostic variables identified only the presence of ascites and ASA score to be independent predictors of prognosis in our dataset, albeit with marginal gain in prognostic information, after accounting for stage and debulking. Conclusions Existing prognostic models for newly diagnosed EOC showed acceptable calibration in our cohort for clinical application. However, modeling of prospective variables in our dataset reiterates that stage and debulking remain the most important predictors of prognosis in this setting. PMID:25620544

An inflammation-based cumulative prognostic score system in patients with diffuse large B cell lymphoma in rituximab era.

PubMed

Sun, Feifei; Zhu, Jia; Lu, Suying; Zhen, Zijun; Wang, Juan; Huang, Junting; Ding, Zonghui; Zeng, Musheng; Sun, Xiaofei

2018-01-02

Systemic inflammatory parameters are associated with poor outcomes in malignant patients. Several inflammation-based cumulative prognostic score systems were established for various solid tumors. However, there is few inflammation based cumulative prognostic score system for patients with diffuse large B cell lymphoma (DLBCL). We retrospectively reviewed 564 adult DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy between Nov 1 2006 and Dec 30 2013 and assessed the prognostic significance of six systemic inflammatory parameters evaluated in previous studies by univariate and multivariate analysis:C-reactive protein(CRP), albumin levels, the lymphocyte-monocyte ratio (LMR), the neutrophil-lymphocyte ratio(NLR), the platelet-lymphocyte ratio(PLR)and fibrinogen levels. Multivariate analysis identified CRP, albumin levels and the LMR are three independent prognostic parameters for overall survival (OS). Based on these three factors, we constructed a novel inflammation-based cumulative prognostic score (ICPS) system. Four risk groups were formed: group ICPS = 0, ICPS = 1, ICPS = 2 and ICPS = 3. Advanced multivariate analysis indicated that the ICPS model is a prognostic score system independent of International Prognostic Index (IPI) for both progression-free survival (PFS) (p < 0.001) and OS (p < 0.001). The 3-year OS for patients with ICPS =0, ICPS =1, ICPS =2 and ICPS =3 were 95.6, 88.2, 76.0 and 62.2%, respectively (p < 0.001). The 3-year PFS for patients with ICPS = 0-1, ICPS = 2 and ICPS = 3 were 84.8, 71.6 and 54.5%, respectively (p < 0.001). The prognostic value of the ICPS model indicated that the degree of systemic inflammatory status was associated with clinical outcomes of patients with DLBCL in rituximab era. The ICPS model was shown to classify risk groups more accurately than any single inflammatory prognostic parameters. These findings may be useful for identifying candidates for further inflammation-related mechanism research or novel anti-inflammation target therapies.

Quantitative Radiomics System Decoding the Tumor Phenotype | Informatics Technology for Cancer Research (ITCR)

Cancer.gov

Our goal is to construct a publicly available computational radiomics system for the objective and automated extraction of quantitative imaging features that we believe will yield biomarkers of greater prognostic value compared with routinely extracted descriptors of tumor size. We will create a generalized, open, portable, and extensible radiomics platform that is widely applicable across cancer types and imaging modalities and describe how we will use lung and head and neck cancers as models to validate our developments.

Prognostic and predictive implications of Sokal, Euro and EUTOS scores in chronic myeloid leukaemia in the imatinib era-experience from a tertiary oncology centre in Southern India.

PubMed

Kuntegowdanahalli, Lakshmaiah Chinnagiriyappa; Kanakasetty, Govind Babu; Thanky, Aditi Harsh; Dasappa, Lokanatha; Jacob, Linu Abraham; Mallekavu, Suresh Babu; Lakkavalli, Rajeev Krishnappa; Kadabur, Lokesh N; Haleshappa, Rudresha Antapura

2016-01-01

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder. Over the years many prognostic models have been developed to better risk stratify this disease at baseline. Sokal, Euro, and EUTOS scores were developed in varied populations initially receiving various therapies. Here we try to identify their predictive and prognostic implication in a larger population of Indian patients with CML-CP (chronic phase) in the imatinib era.

Prognostic factors for specific lower extremity and spinal musculoskeletal injuries identified through medical screening and training load monitoring in professional football (soccer): a systematic review

PubMed Central

Sergeant, Jamie C; Parkes, Matthew J; Callaghan, Michael J

2017-01-01

Background Medical screening and load monitoring procedures are commonly used in professional football to assess factors perceived to be associated with injury. Objectives To identify prognostic factors (PFs) and models for lower extremity and spinal musculoskeletal injuries in professional/elite football players from medical screening and training load monitoring processes. Methods The MEDLINE, AMED, EMBASE, CINAHL Plus, SPORTDiscus and PubMed electronic bibliographic databases were searched (from inception to January 2017). Prospective and retrospective cohort studies of lower extremity and spinal musculoskeletal injury incidence in professional/elite football players aged between 16 and 40 years were included. The Quality in Prognostic Studies appraisal tool and the modified Grading of Recommendations Assessment, Development and Evaluation synthesis approach was used to assess the quality of the evidence. Results Fourteen studies were included. 16 specific lower extremity injury outcomes were identified. No spinal injury outcomes were identified. Meta-analysis was not possible due to heterogeneity and study quality. All evidence related to PFs and specific lower extremity injury outcomes was of very low to low quality. On the few occasions where multiple studies could be used to compare PFs and outcomes, only two factors demonstrated consensus. A history of previous hamstring injuries (HSI) and increasing age may be prognostic for future HSI in male players. Conclusions The assumed ability of medical screening tests to predict specific musculoskeletal injuries is not supported by the current evidence. Screening procedures should currently be considered as benchmarks of function or performance only. The prognostic value of load monitoring modalities is unknown. PMID:29177074

Predictive performance of four frailty measures in an older Australian population

PubMed Central

Widagdo, Imaina S.; Pratt, Nicole; Russell, Mary; Roughead, Elizabeth E.

2015-01-01

Background: there are several different frailty measures available for identifying the frail elderly. However, their predictive performance in an Australian population has not been examined. Objective: to examine the predictive performance of four internationally validated frailty measures in an older Australian population. Methods: a retrospective study in the Australian Longitudinal Study of Ageing (ALSA) with 2,087 participants. Frailty was measured at baseline using frailty phenotype (FP), simplified frailty phenotype (SFP), frailty index (FI) and prognostic frailty score (PFS). Odds ratios (OR) were calculated to measure the association between frailty and outcomes at Wave 3 including mortality, hospitalisation, nursing home admission, fall and a combination of all outcomes. Predictive performance was measured by assessing sensitivity, specificity, positive and negative predictive values (PPV and NPV) and likelihood ratio (LR). Area under the curve (AUC) of dichotomised and the multilevel or continuous model of the measures was examined. Results: prevalence of frailty varied from 2% up to 49% between the measures. Frailty was significantly associated with an increased risk of any outcome, OR (95% confidence interval) for FP: 1.9 (1.4–2.8), SFP: 3.6 (1.5–8.8), FI: 3.4 (2.7–4.3) and PFS: 2.3 (1.8–2.8). PFS had high sensitivity across all outcomes (sensitivity: 55.2–77.1%). The PPV for any outcome was highest for SFP and FI (70.8 and 69.7%, respectively). Only FI had acceptable accuracy in predicting outcomes, AUC: 0.59–0.70. Conclusions: being identified as frail by any of the four measures was associated with an increased risk of outcomes; however, their predictive accuracy varied. PMID:26504118

Elevated osteopontin and thrombospondin expression identifies malignant human breast carcinoma but is not indicative of metastatic status

PubMed Central

Wang-Rodriguez, Jessica; Urquidi, Virginia; Rivard, Amber; Goodison, Steve

2003-01-01

Background Our previous characterization of a human breast tumor metastasis model identified several candidate metastasis genes. The expression of osteopontin (OPN) correlated with the metastatic phenotype, whereas thrombospondin-1 (TSP-1) and tyrosinase-related protein-1 (TYRP-1) correlated with the nonmetastatic phenotype of independent MDA-MB-435 cell lines implanted orthotopically into athymic mice. The aim of the present study was to examine the cellular distribution of these molecules in human breast tissue and to determine whether the relative expression level of these three genes is associated with human breast tumor metastasis. Methods Sixty-eight fresh, frozen specimens including 31 primary infiltrating ductal carcinomas, 22 nodal metastases, 10 fibroadenomas, and five normal breast tissues were evaluated for OPN expression, TSP-1 expression and TYRP-1 expression. Immunohistochemistry was performed to monitor the cellular distribution and to qualitatively assess expression. Quantitative analysis was achieved by enrichment of breast epithelial cells using laser-capture microdissection and subsequent real-time, quantitative PCR. Results The epithelial components of the breast tissue were the source of OPN and TSP-1 expression, whereas TYRP-1 was present in both the epithelial and stromal components. Both OPN and TSP-1 expression were significantly higher in malignant epithelial sources over normal and benign epithelial sources, but no difference in expression levels was evident between primary tumors with or without metastases, nor between primary and metastatic carcinomas. Conclusion Elevated expression of OPN and TSP-1 may play a role in the pathogenesis of breast cancer. The multiplex analysis of these molecules may enhance our ability to diagnose and/or prognosticate human breast malignancy. PMID:12927044

Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans.

PubMed

Tuijnenburg, Paul; Lango Allen, Hana; Burns, Siobhan O; Greene, Daniel; Jansen, Machiel H; Staples, Emily; Stephens, Jonathan; Carss, Keren J; Biasci, Daniele; Baxendale, Helen; Thomas, Moira; Chandra, Anita; Kiani-Alikhan, Sorena; Longhurst, Hilary J; Seneviratne, Suranjith L; Oksenhendler, Eric; Simeoni, Ilenia; de Bree, Godelieve J; Tool, Anton T J; van Leeuwen, Ester M M; Ebberink, Eduard H T M; Meijer, Alexander B; Tuna, Salih; Whitehorn, Deborah; Brown, Matthew; Turro, Ernest; Thrasher, Adrian J; Smith, Kenneth G C; Thaventhiran, James E; Kuijpers, Taco W

2018-03-02

The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21 low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Sox11 expression in astrocytic gliomas: correlation with nestin/c-Met/IDH1-R132H expression phenotypes, p-Stat-3 and survival

PubMed Central

Korkolopoulou, P; Levidou, G; El-Habr, E A; Adamopoulos, C; Fragkou, P; Boviatsis, E; Themistocleous, M S; Petraki, K; Vrettakos, G; Sakalidou, M; Samaras, V; Zisakis, A; Saetta, A; Chatziandreou, I; Patsouris, E; Piperi, C

2013-01-01

Background: Sox11 is a transcription factor expressed in foetal and neoplastic brain tissue, including gliomas. It has been shown to suppress the tumourigenicity of glioma stem cells in vivo, thereby being hypothesised to function as a tumour suppressor. Methods: We investigated the expression of Sox11 in 132 diffuse astrocytomas in relation to the regulator cell marker nestin, c-Met and IDH1-R132H, which have shown to be differentially expressed among the molecular subgroups of malignant gliomas, as well as to an inducer of astrocytic differentiation, that is, signal transducer and activator of transcription (p-STAT-3), clinicopathological features and survival. Results: Sox11 immunoreactivity was identified in all tumours irrespective of grade, but being correlated with p-STAT-3. Three out of seven cases showed partial Sox11 promoter methylation. In >50% of our cases neoplastic cells coexpressed Sox11 and nestin, a finding further confirmed in primary glioblastoma cell cultures. Furthermore, nestin, c-Met and IDH1-R132H expression differed among grade categories. Cluster analysis identified four groups of patients according to c-Met, nestin and IDH1-R132H expression. The c-Met/nestin high-expressor group displayed a higher Sox11 expression. Sox11 expression was an indicator of favourable prognosis in glioblastomas, which remained in multivariate analysis and validated in an independent set of 72 cases. The c-Met/nestin high-expressor group was marginally with shorter survival in univariate analysis. Conclusions: We highlight the importance of Sox11 expression as a favourable prognosticator in glioblastomas. c-Met/nestin/IDH1-R132H expression phenotypes recapitulate the molecular subgroups of malignant glioma. PMID:23619925

Sox11 expression in astrocytic gliomas: correlation with nestin/c-Met/IDH1-R132H expression phenotypes, p-Stat-3 and survival.

PubMed

Korkolopoulou, P; Levidou, G; El-Habr, E A; Adamopoulos, C; Fragkou, P; Boviatsis, E; Themistocleous, M S; Petraki, K; Vrettakos, G; Sakalidou, M; Samaras, V; Zisakis, A; Saetta, A; Chatziandreou, I; Patsouris, E; Piperi, C

2013-05-28

Sox11 is a transcription factor expressed in foetal and neoplastic brain tissue, including gliomas. It has been shown to suppress the tumourigenicity of glioma stem cells in vivo, thereby being hypothesised to function as a tumour suppressor. We investigated the expression of Sox11 in 132 diffuse astrocytomas in relation to the regulator cell marker nestin, c-Met and IDH1-R132H, which have shown to be differentially expressed among the molecular subgroups of malignant gliomas, as well as to an inducer of astrocytic differentiation, that is, signal transducer and activator of transcription (p-STAT-3), clinicopathological features and survival. Sox11 immunoreactivity was identified in all tumours irrespective of grade, but being correlated with p-STAT-3. Three out of seven cases showed partial Sox11 promoter methylation. In >50% of our cases neoplastic cells coexpressed Sox11 and nestin, a finding further confirmed in primary glioblastoma cell cultures. Furthermore, nestin, c-Met and IDH1-R132H expression differed among grade categories. Cluster analysis identified four groups of patients according to c-Met, nestin and IDH1-R132H expression. The c-Met/nestin high-expressor group displayed a higher Sox11 expression. Sox11 expression was an indicator of favourable prognosis in glioblastomas, which remained in multivariate analysis and validated in an independent set of 72 cases. The c-Met/nestin high-expressor group was marginally with shorter survival in univariate analysis. We highlight the importance of Sox11 expression as a favourable prognosticator in glioblastomas. c-Met/nestin/IDH1-R132H expression phenotypes recapitulate the molecular subgroups of malignant glioma.

Advanced Methods for Determining Prediction Uncertainty in Model-Based Prognostics with Application to Planetary Rovers

NASA Technical Reports Server (NTRS)

Daigle, Matthew J.; Sankararaman, Shankar

2013-01-01

Prognostics is centered on predicting the time of and time until adverse events in components, subsystems, and systems. It typically involves both a state estimation phase, in which the current health state of a system is identified, and a prediction phase, in which the state is projected forward in time. Since prognostics is mainly a prediction problem, prognostic approaches cannot avoid uncertainty, which arises due to several sources. Prognostics algorithms must both characterize this uncertainty and incorporate it into the predictions so that informed decisions can be made about the system. In this paper, we describe three methods to solve these problems, including Monte Carlo-, unscented transform-, and first-order reliability-based methods. Using a planetary rover as a case study, we demonstrate and compare the different methods in simulation for battery end-of-discharge prediction.

Incorporating genomic, transcriptomic and clinical data: a prognostic and stem cell-like MYC and PRC imbalance in high-risk neuroblastoma.

PubMed

Yang, Xinan Holly; Tang, Fangming; Shin, Jisu; Cunningham, John M

2017-10-03

Previous studies suggested that cancer cells possess traits reminiscent of the biological mechanisms ascribed to normal embryonic stem cells (ESCs) regulated by MYC and Polycomb repressive complex 2 (PRC2). Several poorly differentiated adult tumors showed preferentially high expression levels in targets of MYC, coincident with low expression levels in targets of PRC2. This paper will reveal this ESC-like cancer signature in high-risk neuroblastoma (HR-NB), the most common extracranial solid tumor in children. We systematically assembled genomic variants, gene expression changes, priori knowledge of gene functions, and clinical outcomes to identify prognostic multigene signatures. First, we assigned a new, individualized prognostic index using the relative expressions between the poor- and good-outcome signature genes. We then characterized HR-NB aggressiveness beyond these prognostic multigene signatures through the imbalanced effects of MYC and PRC2 signaling. We further analyzed Retinoic acid (RA)-induced HR-NB cells to model tumor cell differentiation. Finally, we performed in vitro validation on ZFHX3, a cell differentiation marker silenced by PRC2, and compared cell morphology changes before and after blocking PRC2 in HR-NB cells. A significant concurrence existed between exons with verified variants and genes showing MYCN-dependent expression in HR-NB. From these biomarker candidates, we identified two novel prognostic gene-set pairs with multi-scale oncogenic defects. Intriguingly, MYC targets over-represented an unfavorable component of the identified prognostic signatures while PRC2 targets over-represented a favorable component. The cell cycle arrest and neuronal differentiation marker ZFHX3 was identified as one of PRC2-silenced tumor suppressor candidates. Blocking PRC2 reduced tumor cell growth and increased the mRNA expression levels of ZFHX3 in an early treatment stage. This hypothesis-driven systems bioinformatics work offered novel insights into the PRC2-mediated tumor cell growth and differentiation in neuroblastoma, which may exert oncogenic effects together with MYC regulation. Our results propose a prognostic effect of imbalanced MYC and PRC2 moderations in pediatric HR-NB for the first time. This study demonstrates an incorporation of genomic landscapes and transcriptomic profiles into the hypothesis-driven precision prognosis and biomarker discovery. The application of this approach to neuroblastoma, as well as other cancer more broadly, could contribute to reduced relapse and mortality rates in the long term.

DOME/GALT type adenocarcimoma of the colon: a case report, literature review and a unified phenotypic categorization.

PubMed

Kannuna, Hala; Rubio, Carlos A; Silverio, Patricia Caseiro; Girardin, Marc; Goossens, Nicolas; Rubbia-Brandt, Laura; Puppa, Giacomo

2015-07-09

Several types of colorectal cancers are associated with a prominent lymphoid component, which is considered a positive prognostic factor. We report a case of a dome-type carcinoma of the cecum in a 57 year old female. The sessile, non-polypoid lesion histologically consisted of a tubulovillous adenoma with low-grade dysplasia. The submucosal invasive component showed low-grade architectural features that included cystically dilated glands containing eosinohilic debris. Immunohistochemical studies displayed retention of the four mistmach repair proteins, consistent with a stable phenotype. After 3 years, the patient remains free of recurrence. A literature review highlighted striking similarities between dome-type carcinoma and the gut-associated lymphoid tissue carcinoma, the two sharing an intimate association with the gut associated lymphoid tissue.The two variants might therefore be grouped into a unified category.

Nottingham Prognostic Index Plus (NPI+): a modern clinical decision making tool in breast cancer.

PubMed

Rakha, E A; Soria, D; Green, A R; Lemetre, C; Powe, D G; Nolan, C C; Garibaldi, J M; Ball, G; Ellis, I O

2014-04-02

Current management of breast cancer (BC) relies on risk stratification based on well-defined clinicopathologic factors. Global gene expression profiling studies have demonstrated that BC comprises distinct molecular classes with clinical relevance. In this study, we hypothesised that molecular features of BC are a key driver of tumour behaviour and when coupled with a novel and bespoke application of established clinicopathologic prognostic variables can predict both clinical outcome and relevant therapeutic options more accurately than existing methods. In the current study, a comprehensive panel of biomarkers with relevance to BC was applied to a large and well-characterised series of BC, using immunohistochemistry and different multivariate clustering techniques, to identify the key molecular classes. Subsequently, each class was further stratified using a set of well-defined prognostic clinicopathologic variables. These variables were combined in formulae to prognostically stratify different molecular classes, collectively known as the Nottingham Prognostic Index Plus (NPI+). The NPI+ was then used to predict outcome in the different molecular classes. Seven core molecular classes were identified using a selective panel of 10 biomarkers. Incorporation of clinicopathologic variables in a second-stage analysis resulted in identification of distinct prognostic groups within each molecular class (NPI+). Outcome analysis showed that using the bespoke NPI formulae for each biological BC class provides improved patient outcome stratification superior to the traditional NPI. This study provides proof-of-principle evidence for the use of NPI+ in supporting improved individualised clinical decision making.

FDG-PET/CT at the end of immuno-chemotherapy in follicular lymphoma: the prognostic role of the ratio between target lesion and liver SUVmax (rPET).

PubMed

Annunziata, Salvatore; Cuccaro, Annarosa; Tisi, Maria Chiara; Hohaus, Stefan; Rufini, Vittoria

2018-06-01

To retrospectively investigate the prognostic role of the ratio between target lesion and liver SUV max (rPET) in patients with follicular lymphoma (FL) submitted to FDG-PET/CT at the end of immuno-chemotherapy (PI-PET), and to compare rPET with International Harmonization Project criteria (IHP), Deauville Score (5p-DS) and FL International Prognostic Index at diagnosis (FLIPI). Eighty-nine patients with FL undergoing PI-PET were evaluated. The receiver operating characteristic (ROC) approach was applied to identify the optimal cut-point of rPET with respect to 5-years progression free survival (PFS). The prognostic significance of rPET was compared with IHP, DS and FLIPI. Positive predictive value (PPV) and negative predictive value (NPV) were calculated using the presence of adverse events as gold standard. The ROC analysis for rPET as predictor of progression showed an optimal rPET cut-point of 0.98. Patients with positive values of IHP, DS and rPET had a PFS of 50, 30 and 31%. PPV were of 56, 80 and 80%, NPV of 83, 86 and 88%, respectively. DS and rPET differed only in two patients. FLIPI was not predictive of progression and relapse. rPET is a prognostic factor in patients with FL submitted to PI-PET. Although it has a similar prognostic power as DS, it can have methodological advantages over visual analysis. PI-PET with different evaluation systems has a stronger prognostic power than FLIPI at diagnosis, so it could be useful to identify patients with FL at risk for early relapse after immuno-chemotherapy.

Molecular profiling identifies prognostic markers of stage IA lung adenocarcinoma.

PubMed

Zhang, Jie; Shao, Jinchen; Zhu, Lei; Zhao, Ruiying; Xing, Jie; Wang, Jun; Guo, Xiaohui; Tu, Shichun; Han, Baohui; Yu, Keke

2017-09-26

We previously showed that different pathologic subtypes were associated with different prognostic values in patients with stage IA lung adenocarcinoma (AC). We hypothesize that differential gene expression profiles of different subtypes may be valuable factors for prognosis in stage IA lung adenocarcinoma. We performed microarray gene expression profiling on tumor tissues micro-dissected from patients with acinar and solid predominant subtypes of stage IA lung adenocarcinoma. These patients had undergone a lobectomy and mediastinal lymph node dissection at the Shanghai Chest Hospital, Shanghai, China in 2012. No patient had preoperative treatment. We performed the Gene Set Enrichment Analysis (GSEA) analysis to look for gene expression signatures associated with tumor subtypes. The histologic subtypes of all patients were classified according to the 2015 WHO lung Adenocarcinoma classification. We found that patients with the solid predominant subtype are enriched for genes involved in RNA polymerase activity as well as inactivation of the p53 pathway. Further, we identified a list of genes that may serve as prognostic markers for stage IA lung adenocarcinoma. Validation in the TCGA database shows that these genes are correlated with survival, suggesting that they are novel prognostic factors for stage IA lung adenocarcinoma. In conclusion, we have uncovered novel prognostic factors for stage IA lung adenocarcinoma using gene expression profiling in combination with histopathology subtyping.

Deep phenotyping to predict live birth outcomes in in vitro fertilization

PubMed Central

Banerjee, Prajna; Choi, Bokyung; Shahine, Lora K.; Jun, Sunny H.; O’Leary, Kathleen; Lathi, Ruth B.; Westphal, Lynn M.; Wong, Wing H.; Yao, Mylene W. M.

2010-01-01

Nearly 75% of in vitro fertilization (IVF) treatments do not result in live births and patients are largely guided by a generalized age-based prognostic stratification. We sought to provide personalized and validated prognosis by using available clinical and embryo data from prior, failed treatments to predict live birth probabilities in the subsequent treatment. We generated a boosted tree model, IVFBT, by training it with IVF outcomes data from 1,676 first cycles (C1s) from 2003–2006, followed by external validation with 634 cycles from 2007–2008, respectively. We tested whether this model could predict the probability of having a live birth in the subsequent treatment (C2). By using nondeterministic methods to identify prognostic factors and their relative nonredundant contribution, we generated a prediction model, IVFBT, that was superior to the age-based control by providing over 1,000-fold improvement to fit new data (p < 0.05), and increased discrimination by receiver–operative characteristic analysis (area-under-the-curve, 0.80 vs. 0.68 for C1, 0.68 vs. 0.58 for C2). IVFBT provided predictions that were more accurate for ∼83% of C1 and ∼60% of C2 cycles that were out of the range predicted by age. Over half of those patients were reclassified to have higher live birth probabilities. We showed that data from a prior cycle could be used effectively to provide personalized and validated live birth probabilities in a subsequent cycle. Our approach may be replicated and further validated in other IVF clinics. PMID:20643955

Chronic kidney disease and worsening renal function in acute heart failure: different phenotypes with similar prognostic impact?

PubMed

Palazzuoli, Alberto; Lombardi, Carlo; Ruocco, Gaetano; Padeletti, Margherita; Nuti, Ranuccio; Metra, Marco; Ronco, Claudio

2016-12-01

Nearly a third of patients with acute heart failure experience concomitant renal dysfunction. This condition is often associated with increased costs of care, length of hospitalisation and high mortality. Although the clinical impact of chronic kidney disease (CKD) has been well established, the exact clinical significance of worsening renal function (WRF) during the acute and post-hospitalisation phases is not completely understood. Therefore, it is still unclear which of the common laboratory markers are able to identify WRF at an early stage. Recent studies comparing CKD with WRF showed contradictory results; this could depend on a different WRF definition, clinical characteristics, haemodynamic disorders and the presence of prior renal dysfunction in the population enrolled. The current definition of acute cardiorenal syndrome focuses on both the heart and kidney but it lacks precise laboratory marker cut-offs and a specific diagnostic approach. WRF and CKD could represent different pathophysiological mechanisms in the setting of acute heart failure; the traditional view includes reduced cardiac output with systemic and renal vasoconstriction. Nevertheless, it has become a mixed model that encompasses both forward and backward haemodynamic dysfunction. Increased central venous pressure, renal congestion with tubular obliteration, tubulo-glomerular feedback and increased abdominal pressure are all potential additional contributors. The impact of WRF on patients who experience preserved renal function and individuals affected with CKD is currently unknown. Therefore it is extremely important to understand the origins, the clinical significance and the prognostic impact of WRF on CKD. © The European Society of Cardiology 2015.

Classifying lower grade glioma cases according to whole genome gene expression.

PubMed

Chen, Baoshi; Liang, Tingyu; Yang, Pei; Wang, Haoyuan; Liu, Yanwei; Yang, Fan; You, Gan

2016-11-08

To identify a gene-based signature as a novel prognostic model in lower grade gliomas. A gene signature developed from HOXA7, SLC2A4RG and MN1 could segregate patients into low and high risk score groups with different overall survival (OS), and was validated in TCGA RNA-seq and GSE16011 mRNA array datasets. Receiver operating characteristic (ROC) was performed to show that the three-gene signature was more sensitive and specific than histology, grade, age, IDH1 mutation and 1p/19q co-deletion. Gene Set Enrichment Analysis (GSEA) and GO analysis showed high-risk samples were associated with tumor associated macrophages (TAMs) and highly invasive phenotypes. Moreover, HOXA7-siRNA inhibited migration and invasion in vitro, and downregulated MMP9 at the protein level in U251 glioma cells. A cohort of 164 glioma specimens from the Chinese Glioma Genome Atlas (CGGA) array database were assessed as the training group. TCGA RNA-seq and GSE16011 mRNA array datasets were used for validation. Regression analyses and linear risk score assessment were performed for the identification of the three-gene signature comprising HOXA7, SLC2A4RG and MN1. We established a three-gene signature for lower grade gliomas, which could independently predict overall survival (OS) of lower grade glioma patients with higher sensitivity and specificity compared with other clinical characteristics. These findings indicate that the three-gene signature is a new prognostic model that could provide improved OS prediction and accurate therapies for lower grade glioma patients.

Age but not Philadelphia positivity impairs outcome in older/elderly patients with acute lymphoblastic leukemia in Sweden.

PubMed

Kozlowski, Piotr; Lennmyr, Emma; Ahlberg, Lucia; Bernell, Per; Hulegårdh, Erik; Karbach, Holger; Karlsson, Karin; Tomaszewska-Toporska, Beata; Åström, Maria; Hallböök, Heléne

2017-08-01

Older/elderly patients with acute lymphoblastic leukemia (ALL) are poorly represented in clinical trials. Using Swedish national leukemia registries, we investigated disease/patient characteristics, treatment choices, outcome, and the impact of an age-adapted protocol (introduced in 2009) in this population-based study of patients aged 55-85 years, diagnosed with ALL 2005-2012. Of 174 patients, 82% had B-phenotype, 11% Burkitt leukemia (excluded), and 7% T-phenotype. Philadelphia chromosome positivity (Ph+) occurred in 35%. Of the 155 B- and T-ALL patients, 80% were treated with intensive protocols, and 20% with a palliative approach. Higher age and WHO performance status ≥2 influenced the choice of palliation. Intensive, palliative, and both approaches resulted in complete remission rate 83/16/70% and 3-year overall survival (OS) 32/3/26%. The age-adapted protocol did not improve outcome. With intensive treatment, platelet count ≤35×10 9 /L and age ≥75 years were adverse prognostic factors for OS, Ph+ was not. Male sex was an adverse prognostic factor in the 55-64 year age-group. We report a high frequency of Ph+ in older/elderly patients, with no evidence of poorer outcome compared to Ph-negative disease. Overall prognosis for elderly patients with ALL remains dismal, despite the use of age-adapted treatment. © 2017 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.

Prognostic and Predictive Value of CpG Island Methylator Phenotype in Patients with Locally Advanced Nonmetastatic Sporadic Colorectal Cancer

PubMed Central

Long, Yadong; Xu, Ye; Guan, Zuqing; Lian, Peng; Peng, Junjie

2014-01-01

Purpose. In the present study, the prognostic significance of CpG island methylator phenotype (CIMP) in stage II/III sporadic colorectal cancer was evaluated using a five-gene panel. Methods. Fifty stage II/III colorectal cancer patients who received radical resection were included in this study. Promoter methylation of p14ARF, hMLH1, p16INK4a, MGMT, and MINT1 was determined by methylation specific polymerase chain reaction (MSP). CIMP positive was defined as hypermethylation of three or more of the five genes. Impact factors on disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan-Meier method (log-rank test) and adjusted Cox proportional hazards model. Results. Twenty-four percent (12/50) of patients were characterized as CIMP positive. Univariate analysis showed stage III (P = 0.049) and CIMP positive (P = 0.014) patients who had significantly inferior DFS. In Cox regression analysis, CIMP positive epigenotype was independently related with poor DFS with HR = 2.935 and 95% CI: 1.193–7.220 (P = 0.019). In patients with CIMP positive tumor, those receiving adjuvant chemotherapy had a poor DFS than those without adjuvant chemotherapy (P = 0.023). Conclusions. CIMP positive was significantly correlated with decreased DFS in stage II/III colorectal cancer. Patients with CIMP positive locally advanced sporadic colorectal cancers may not benefit from 5-fluorouracil based adjuvant chemotherapy. PMID:24822060

Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis

PubMed Central

Garg, Abhishek D.; De Ruysscher, Dirk; Agostinis, Patrizia

2016-01-01

ABSTRACT The emerging role of the cancer cell-immune cell interface in shaping tumorigenesis/anticancer immunotherapy has increased the need to identify prognostic biomarkers. Henceforth, our primary aim was to identify the immunogenic cell death (ICD)-derived metagene signatures in breast, lung and ovarian cancer that associate with improved patient survival. To this end, we analyzed the prognostic impact of differential gene-expression of 33 pre-clinically-validated ICD-parameters through a large-scale meta-analysis involving 3,983 patients (‘discovery’ dataset) across lung (1,432), breast (1,115) and ovarian (1,436) malignancies. The main results were also substantiated in ‘validation’ datasets consisting of 818 patients of same cancer-types (i.e. 285 breast/274 lung/259 ovarian). The ICD-associated parameters exhibited a highly-clustered and largely cancer type-specific prognostic impact. Interestingly, we delineated ICD-derived consensus-metagene signatures that exhibited a positive prognostic impact that was either cancer type-independent or specific. Importantly, most of these ICD-derived consensus-metagenes (acted as attractor-metagenes and thereby) ‘attracted’ highly co-expressing sets of genes or convergent-metagenes. These convergent-metagenes also exhibited positive prognostic impact in respective cancer types. Remarkably, we found that the cancer type-independent consensus-metagene acted as an ‘attractor’ for cancer-specific convergent-metagenes. This reaffirms that the immunological prognostic landscape of cancer tends to segregate between cancer-independent and cancer-type specific gene signatures. Moreover, this prognostic landscape was largely dominated by the classical T cell activity/infiltration/function-related biomarkers. Interestingly, each cancer type tended to associate with biomarkers representing a specific T cell activity or function rather than pan-T cell biomarkers. Thus, our analysis confirms that ICD can serve as a platform for discovery of novel prognostic metagenes. PMID:27057433

High Myeloperoxidase Positive Cell Infiltration in Colorectal Cancer Is an Independent Favorable Prognostic Factor

PubMed Central

Eppenberger-Castori, Serenella; Zlobec, Inti; Viehl, Carsten T.; Frey, Daniel M.; Nebiker, Christian A.; Rosso, Raffaele; Zuber, Markus; Amicarella, Francesca; Iezzi, Giandomenica; Sconocchia, Giuseppe; Heberer, Michael; Lugli, Alessandro; Tornillo, Luigi; Oertli, Daniel

2013-01-01

Background Colorectal cancer (CRC) infiltration by adaptive immune system cells correlates with favorable prognosis. The role of the innate immune system is still debated. Here we addressed the prognostic impact of CRC infiltration by neutrophil granulocytes (NG). Methods A TMA including healthy mucosa and clinically annotated CRC specimens (n = 1491) was stained with MPO and CD15 specific antibodies. MPO+ and CD15+ positive immune cells were counted by three independent observers. Phenotypic profiles of CRC infiltrating MPO+ and CD15+ cells were validated by flow cytometry on cell suspensions derived from enzymatically digested surgical specimens. Survival analysis was performed by splitting randomized data in training and validation subsets. Results MPO+ and CD15+ cell infiltration were significantly correlated (p<0.0001; r = 0.76). However, only high density of MPO+ cell infiltration was associated with significantly improved survival in training (P = 0.038) and validation (P = 0.002) sets. In multivariate analysis including T and N stage, vascular invasion, tumor border configuration and microsatellite instability status, MPO+ cell infiltration proved an independent prognostic marker overall (P = 0.004; HR = 0.65; CI:±0.15) and in both training (P = 0.048) and validation (P = 0.036) sets. Flow-cytometry analysis of CRC cell suspensions derived from clinical specimens showed that while MPO+ cells were largely CD15+/CD66b+, sizeable percentages of CD15+ and CD66b+ cells were MPO−. Conclusions High density MPO+ cell infiltration is a novel independent favorable prognostic factor in CRC. PMID:23734221

Comparison of the prognostic utility of the revised International Prognostic Scoring System and the French Prognostic Scoring System in azacitidine-treated patients with myelodysplastic syndromes.

PubMed

Zeidan, Amer M; Lee, Ju-Whei; Prebet, Thomas; Greenberg, Peter; Sun, Zhuoxin; Juckett, Mark; Smith, Mitchell R; Paietta, Elisabeth; Gabrilove, Janice; Erba, Harry P; Tallman, Martin S; Gore, Steven D

2014-08-01

The revised International Prognostic Scoring System (IPSS-R) was developed in a cohort of untreated myelodysplastic syndromes (MDS) patients. A French Prognostic Scoring System (FPSS) was recently reported to identify differential survival among azacitidine-treated patients with high-risk MDS. We applied the FPSS and IPSS-R to 150 patients previously randomized to azacitidine monotherapy or a combination of azacitidine with entinostat (a histone deacetylase inhibitor). Neither score predicted response but both discriminated patients with different overall survival (OS; median OS, FPSS: 9·7, 14·7, and 25·3 months, P = 0·018; IPSS-R: 12·5, 11·3, 20·8, and 36 months, P = 0·005). Statistical analysis suggested no improvement in OS prediction for the FPSS over the IPSS-R in azacitidine-treated patients. © 2014 John Wiley & Sons Ltd.

Circulating B cells in type 1 diabetics exhibit fewer maturation-associated phenotypes.

PubMed

Hanley, Patrick; Sutter, Jennifer A; Goodman, Noah G; Du, Yangzhu; Sekiguchi, Debora R; Meng, Wenzhao; Rickels, Michael R; Naji, Ali; Luning Prak, Eline T

2017-10-01

Although autoantibodies have been used for decades as diagnostic and prognostic markers in type 1 diabetes (T1D), further analysis of developmental abnormalities in B cells could reveal tolerance checkpoint defects that could improve individualized therapy. To evaluate B cell developmental progression in T1D, immunophenotyping was used to classify circulating B cells into transitional, mature naïve, mature activated, and resting memory subsets. Then each subset was analyzed for the expression of additional maturation-associated markers. While the frequencies of B cell subsets did not differ significantly between patients and controls, some T1D subjects exhibited reduced proportions of B cells that expressed transmembrane activator and CAML interactor (TACI) and Fas receptor (FasR). Furthermore, some T1D subjects had B cell subsets with lower frequencies of class switching. These results suggest circulating B cells exhibit variable maturation phenotypes in T1D. These phenotypic variations may correlate with differences in B cell selection in individual T1D patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

SNP-associations and phenotype predictions from hundreds of microbial genomes without genome alignments.

PubMed

Hall, Barry G

2014-01-01

SNP-association studies are a starting point for identifying genes that may be responsible for specific phenotypes, such as disease traits. The vast bulk of tools for SNP-association studies are directed toward SNPs in the human genome, and I am unaware of any tools designed specifically for such studies in bacterial or viral genomes. The PPFS (Predict Phenotypes From SNPs) package described here is an add-on to kSNP , a program that can identify SNPs in a data set of hundreds of microbial genomes. PPFS identifies those SNPs that are non-randomly associated with a phenotype based on the χ² probability, then uses those diagnostic SNPs for two distinct, but related, purposes: (1) to predict the phenotypes of strains whose phenotypes are unknown, and (2) to identify those diagnostic SNPs that are most likely to be causally related to the phenotype. In the example illustrated here, from a set of 68 E. coli genomes, for 67 of which the pathogenicity phenotype was known, there were 418,500 SNPs. Using the phenotypes of 36 of those strains, PPFS identified 207 diagnostic SNPs. The diagnostic SNPs predicted the phenotypes of all of the genomes with 97% accuracy. It then identified 97 SNPs whose probability of being causally related to the pathogenic phenotype was >0.999. In a second example, from a set of 116 E. coli genome sequences, using the phenotypes of 65 strains PPFS identified 101 SNPs that predicted the source host (human or non-human) with 90% accuracy.

MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status.

PubMed

Bady, Pierre; Sciuscio, Davide; Diserens, Annie-Claire; Bloch, Jocelyne; van den Bent, Martin J; Marosi, Christine; Dietrich, Pierre-Yves; Weller, Michael; Mariani, Luigi; Heppner, Frank L; Mcdonald, David R; Lacombe, Denis; Stupp, Roger; Delorenzi, Mauro; Hegi, Monika E

2012-10-01

The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg12434587 [corrected] and cg12981137 provided good classification properties and prognostic value (kappa = 0.85; log-rank p < 0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom MGMT methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27 was successfully validated in an independent cohort of chemo-radiotherapy-treated glioblastoma patients (n = 50; kappa = 0.88; outcome, log-rank p < 0.001). Lower prevalence of MGMT methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome Atlas than in low grade and anaplastic glioma cohorts, while in CIMP-negative gliomas MGMT was classified as methylated in approximately 50 % regardless of tumor grade. The proposed MGMT-STP27 prediction model allows mining of datasets derived on the HM-450K or HM-27K BeadChip to explore effects of distinct epigenetic context of MGMT methylation suspected to modulate treatment resistance in different tumor types.

Clinical and Prognostic Profiles of Cardiomyopathies Caused by Mutations in the Troponin T Gene.

PubMed

Ripoll-Vera, Tomás; Gámez, José María; Govea, Nancy; Gómez, Yolanda; Núñez, Juana; Socías, Lorenzo; Escandell, Ángela; Rosell, Jorge

2016-02-01

Mutations in the troponin T gene (TTNT2) have been associated in small studies with the development of hypertrophic cardiomyopathy characterized by a high risk of sudden death and mild hypertrophy. We describe the clinical course of patients carrying mutations in this gene. We analyzed the clinical characteristics and prognosis of patients with mutations in the TNNT2 gene who were seen in an inherited cardiac disease unit. Of 180 families with genetically studied cardiomyopathies, 21 families (11.7%) were identified as having mutations in TNNT2: 10 families had Arg92Gln, 5 had Arg286His, 3 had Arg278Cys, 1 had Arg92Trp, 1 had Arg94His, and 1 had Ile221Thr. Thirty-three additional genetic carriers were identified through family assessment. The study included 54 genetic carriers: 56% were male, and the mean average age was 41 ± 17 years. There were 33 cases of hypertrophic cardiomyopathy, 9 of dilated cardiomyopathy, and 1 of noncompaction cardiomyopathy, and maximal myocardial thickness was 18.5 ± 6mm. Ventricular dysfunction was present in 30% of individuals and a history of sudden death in 62%. During follow-up, 4 patients died and 14 (33%) received a defibrillator (8 probands, 6 relatives). Mean survival was 54 years. Carriers of Arg92Gln had early disease development, high penetrance, a high risk of sudden death, a high rate of defibrillator implantation, and a high frequency of mixed phenotype. Mutations in the TNNT2 gene were more common in this series than in previous studies. The clinical and prognostic profiles depended on the mutation present. Carriers of the Arg92Gln mutation developed hypertrophic or dilated cardiomyopathy and had a significantly worse prognosis than those with other mutations in TNNT2 or other sarcomeric genes. Copyright © 2015 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Intrinsic Molecular Subtypes of Glioma Are Prognostic and Predict Benefit From Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Combination With Other Prognostic Factors in Anaplastic Oligodendroglial Brain Tumors: A Report From EORTC Study 26951

PubMed Central

Erdem-Eraslan, Lale; Gravendeel, Lonneke A.; de Rooi, Johan; Eilers, Paul H.C.; Idbaih, Ahmed; Spliet, Wim G.M.; den Dunnen, Wilfred F.A.; Teepen, Johannes L.; Wesseling, Pieter; Sillevis Smitt, Peter A.E.; Kros, Johan M.; Gorlia, Thierry; van den Bent, Martin J.; French, Pim J.

2013-01-01

Purpose Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a randomized phase III clinical trial investigating adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study includes gene expression profiles of formalin-fixed, paraffin-embedded (FFPE) clinical trial samples. Patients and Methods Gene expression profiling was performed in 140 samples, 47 fresh frozen samples and 93 FFPE samples, on HU133_Plus_2.0 and HuEx_1.0_st arrays, respectively. Results All previously identified six IGSs are present in EORTC 26951. This confirms that different molecular subtypes are present within a well-defined histologic subtype. Intrinsic subtypes are highly prognostic for overall survival (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance status, and tumor location), molecular (1p/19q loss of heterozygosity [LOH], IDH1 mutation, and MGMT methylation), and histologic parameters. Combining known molecular (1p/19q LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (proportion of explained variation, 30% v 23% for each individual group of factors). Specific genetic changes (IDH1, 1p/19q LOH, and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p/19q LOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone versus 12.8 years after RT/PCV (P = .0349; hazard ratio, 2.18; 95% CI, 1.06 to 4.50). Conclusion Intrinsic subtypes are highly prognostic in EORTC 26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV. PMID:23269986

Selection for inpatient rehabilitation after acute stroke: a systematic review of the literature.

PubMed

Hakkennes, Sharon J; Brock, Kim; Hill, Keith D

2011-12-01

To identify patient-related factors that have been found to correlate with functional outcomes post acute stroke to guide clinical decision making with regard to rehabilitation admission after acute stroke. We systematically searched the scientific literature between 1966 and January 2010. The primary source of studies was the electronic databases Medline, CINAHL, and Embase. The search was supplemented with citation tracking. Two reviewers independently applied the inclusion criteria to identify relevant articles from the citations obtained through the literature search. Eligible studies included systematic reviews of prognostic indicators, studies of prognostic indicators of acute discharge disposition, and studies of rehabilitation admission criteria after acute stroke. Of the 8895 studies identified, 83 articles, representing 79 studies, were included in the review. One reviewer extracted the data relating to the participants, prognostic indicators, and outcomes. A second reviewer independently checked data extracted with disagreement resolved by a third reviewer. Quality of included studies was assessed for internal and external validity. Of the 79 studies, 26 were systematic reviews of prognostic indicators of functional level and/or discharge disposition, 48 were studies of prognostic indicators of acute discharge disposition, and 6 were studies of rehabilitation selection criteria. The methodologic quality of the included studies was generally poor. Age, cognition, functional level after stroke, and, to a lesser extent, continence were found to have a consistent association with outcome across all 3 research areas. In addition, stroke severity was also associated with acute discharge disposition, final discharge disposition, and functional level. Sex and side of stroke appeared to have no association across all 3 of the research areas. This review highlights a number of important prognostic indicators and rehabilitation selection criteria that may assist clinicians in improving selection procedures and standardizing access to inpatient rehabilitation after stroke, although the quality of many studies is low. Further high quality studies and reviews of prognostic indicators and clinician decision making with regards to rehabilitation acceptance are required. Copyright © 2011 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Comparative effectiveness of incorporating a hypothetical DCIS prognostic marker into breast cancer screening.

PubMed

Trentham-Dietz, Amy; Ergun, Mehmet Ali; Alagoz, Oguzhan; Stout, Natasha K; Gangnon, Ronald E; Hampton, John M; Dittus, Kim; James, Ted A; Vacek, Pamela M; Herschorn, Sally D; Burnside, Elizabeth S; Tosteson, Anna N A; Weaver, Donald L; Sprague, Brian L

2018-02-01

Due to limitations in the ability to identify non-progressive disease, ductal carcinoma in situ (DCIS) is usually managed similarly to localized invasive breast cancer. We used simulation modeling to evaluate the potential impact of a hypothetical test that identifies non-progressive DCIS. A discrete-event model simulated a cohort of U.S. women undergoing digital screening mammography. All women diagnosed with DCIS underwent the hypothetical DCIS prognostic test. Women with test results indicating progressive DCIS received standard breast cancer treatment and a decrement to quality of life corresponding to the treatment. If the DCIS test indicated non-progressive DCIS, no treatment was received and women continued routine annual surveillance mammography. A range of test performance characteristics and prevalence of non-progressive disease were simulated. Analysis compared discounted quality-adjusted life years (QALYs) and costs for test scenarios to base-case scenarios without the test. Compared to the base case, a perfect prognostic test resulted in a 40% decrease in treatment costs, from $13,321 to $8005 USD per DCIS case. A perfect test produced 0.04 additional QALYs (16 days) for women diagnosed with DCIS, added to the base case of 5.88 QALYs per DCIS case. The results were sensitive to the performance characteristics of the prognostic test, the proportion of DCIS cases that were non-progressive in the model, and the frequency of mammography screening in the population. A prognostic test that identifies non-progressive DCIS would substantially reduce treatment costs but result in only modest improvements in quality of life when averaged over all DCIS cases.

Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

DTIC Science & Technology

2010-06-01

mutation si gnature i s prognostic in EGFR wild-type l ung adenocarcinomas and identifies Metastasis associated in colon cancer 1 (MACC1) as an EGFR...T790M mutation (N=7, blue curve) (AUC: area under the curve). Figure 3. EGFR dependency signature is a favorable prognostic factor. EGFR index...developed. T he si gnature w as shown t o b e prognostic regardless of EGFR status. T he results also suggest MACC1 to be a regulator of MET in NSCLC

On Applying the Prognostic Performance Metrics

NASA Technical Reports Server (NTRS)

Saxena, Abhinav; Celaya, Jose; Saha, Bhaskar; Saha, Sankalita; Goebel, Kai

2009-01-01

Prognostics performance evaluation has gained significant attention in the past few years. As prognostics technology matures and more sophisticated methods for prognostic uncertainty management are developed, a standardized methodology for performance evaluation becomes extremely important to guide improvement efforts in a constructive manner. This paper is in continuation of previous efforts where several new evaluation metrics tailored for prognostics were introduced and were shown to effectively evaluate various algorithms as compared to other conventional metrics. Specifically, this paper presents a detailed discussion on how these metrics should be interpreted and used. Several shortcomings identified, while applying these metrics to a variety of real applications, are also summarized along with discussions that attempt to alleviate these problems. Further, these metrics have been enhanced to include the capability of incorporating probability distribution information from prognostic algorithms as opposed to evaluation based on point estimates only. Several methods have been suggested and guidelines have been provided to help choose one method over another based on probability distribution characteristics. These approaches also offer a convenient and intuitive visualization of algorithm performance with respect to some of these new metrics like prognostic horizon and alpha-lambda performance, and also quantify the corresponding performance while incorporating the uncertainty information.

Assessing CpG island methylator phenotype, 1p/19q codeletion, and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial

PubMed Central

Wiestler, Benedikt; Capper, David; Hovestadt, Volker; Sill, Martin; Jones, David T.W.; Hartmann, Christian; Felsberg, Joerg; Platten, Michael; Feiden, Wolfgang; Keyvani, Kathy; Pfister, Stefan M.; Wiestler, Otmar D.; Meyermann, Richard; Reifenberger, Guido; Pietsch, Thorsten; von Deimling, Andreas; Weller, Michael; Wick, Wolfgang

2014-01-01

Background Molecular biomarkers including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q codeletion, and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation may improve prognostication and guide treatment decisions for patients with World Health Organization (WHO) anaplastic gliomas. At present, each marker is individually tested by distinct assays. Illumina Infinium HumanMethylation450 BeadChip arrays (HM450) enable the determination of large-scale methylation profiles and genome-wide DNA copy number changes. Algorithms have been developed to detect the glioma CpG island methylator phenotype (G-CIMP) associated with IDH1/2 mutation, 1p/19q codeletion, and MGMT promoter methylation using a single assay. Methods Here, we retrospectively investigated the diagnostic and prognostic performance of these algorithms in comparison to individual marker testing and patient outcome in the biomarker cohort (n = 115 patients) of the NOA-04 trial. Results Concordance for IDH and 1p/19q status was very high: In 92% of samples, the HM450 and reference data agreed. In discordant samples, survival analysis by Kaplan-Meier and Cox regression analyses suggested a more accurate assessment of biological phenotype by the HM450 analysis. The HM450-derived MGMT-STP27 model to calculate MGMT promoter methylation probability revealed this aberration in a significantly higher fraction of samples than conventional methylation-specific PCR, with 87 of 91 G-CIMP tumors predicted as MGMT promoter-methylated. Pyrosequencing of discordant samples confirmed the HM450 assessment in 14 of 17 cases. Conclusions G-CIMP and 1p/19q codeletion are reliably detectable by HM450 analysis and are associated with prognosis in the NOA-04 trial. For MGMT, HM450 suggests promoter methylation in the vast majority of G-CIMP tumors, which is supported by pyrosequencing. PMID:25028501

Severe psychomotor delay in a severe presentation of cat-eye syndrome.

PubMed

Jedraszak, Guillaume; Receveur, Aline; Andrieux, Joris; Mathieu-Dramard, Michèle; Copin, Henri; Morin, Gilles

2015-01-01

Cat-eye syndrome is a rare genetic syndrome of chromosomal origin. Individuals with cat-eye syndrome are characterized by the presence of preauricular pits and/or tags, anal atresia, and iris coloboma. Many reported cases also presented with variable congenital anomalies and intellectual disability. Most patients diagnosed with CES carry a small supernumerary bisatellited marker chromosome, resulting in partial tetrasomy of 22p-22q11.21. There are two types of small supernumerary marker chromosome, depending on the breakpoint site. In a very small proportion of cases, other cytogenetic anomalies are reportedly associated with the cat-eye syndrome phenotype. Here, we report a patient with cat-eye syndrome caused by a type 1 small supernumerary marker chromosome. The phenotype was atypical and included a severe developmental delay. The use of array comparative genomic hybridization ruled out the involvement of another chromosomal imbalance in the neurological phenotype. In the literature, only a few patients with cat-eye syndrome present with a severe developmental delay, and all of the latter carried an atypical partial trisomy 22 or an uncharacterized small supernumerary marker chromosome. Hence, this is the first report of a severe neurological phenotype in cat-eye syndrome with a typical type 1 small supernumerary marker chromosome. Our observation clearly complicates prognostic assessment, particularly when cat-eye syndrome is diagnosed prenatally.

Two-protein signature of novel serological markers apolipoprotein-A2 and serum amyloid alpha predicts prognosis in patients with metastatic renal cell cancer and improves the currently used prognostic survival models.

PubMed

Vermaat, J S; van der Tweel, I; Mehra, N; Sleijfer, S; Haanen, J B; Roodhart, J M; Engwegen, J Y; Korse, C M; Langenberg, M H; Kruit, W; Groenewegen, G; Giles, R H; Schellens, J H; Beijnen, J H; Voest, E E

2010-07-01

In metastatic renal cell cancer (mRCC), the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model is widely used for clinical trial design and patient management. To improve prognostication, we applied proteomics to identify novel serological proteins associated with overall survival (OS). Sera from 114 mRCC patients were screened by surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS). Identified proteins were related to OS. Three proteins were subsequently validated with enzyme-linked immunosorbent assays and immunoturbidimetry. Prognostic models were statistically bootstrapped to correct for overestimation. SELDI-TOF MS detected 10 proteins associated with OS. Of these, apolipoprotein A2 (ApoA2), serum amyloid alpha (SAA) and transthyretin were validated for their association with OS (P = 5.5 x 10(-9), P = 1.1 x 10(-7) and P = 0.0004, respectively). Combining ApoA2 and SAA yielded a prognostic two-protein signature [Akaike's Information Criteria (AIC) = 732, P = 5.2 x 10(-7)]. Including previously identified prognostic factors, multivariable Cox regression analysis revealed ApoA2, SAA, lactate dehydrogenase, performance status and number of metastasis sites as independent factors for survival. Using these five factors, categorization of patients into three risk groups generated a novel protein-based model predicting patient prognosis (AIC = 713, P = 4.3 x 10(-11)) more robustly than the MSKCC model (AIC = 729, P = 1.3 x 10(-7)). Applying this protein-based model instead of the MSKCC model would have changed the risk group in 38% of the patients. Proteomics and subsequent validation yielded two novel prognostic markers and survival models which improved prediction of OS in mRCC patients over commonly used risk models. Implementation of these models has the potential to improve current risk stratification, although prospective validation will still be necessary.

Serum C-reactive protein (CRP) as a simple and independent prognostic factor in extranodal natural killer/T-cell lymphoma, nasal type.

PubMed

Li, Ya-Jun; Li, Zhi-Ming; Xia, Yi; Huang, Jia-Jia; Huang, Hui-Qiang; Xia, Zhong-Jun; Lin, Tong-Yu; Li, Su; Cai, Xiu-Yu; Wu-Xiao, Zhi-Jun; Jiang, Wen-Qi

2013-01-01

C-reactive protein (CRP) is a biomarker of the inflammatory response, and it shows significant prognostic value for several types of solid tumors. The prognostic significance of CRP for lymphoma has not been fully examined. We evaluated the prognostic role of baseline serum CRP levels in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTL). We retrospectively analyzed 185 patients with newly diagnosed ENKTL. The prognostic value of the serum CRP level was evaluated for the low-CRP group (CRP≤10 mg/L) versus the high-CRP group (CRP>10 mg/L). The prognostic value of the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI) were evaluated and compared with the newly developed prognostic model. Patients in the high-CRP group tended to display increased adverse clinical characteristics, lower rates of complete remission (P<0.001), inferior progression-free survival (PFS, P = 0.001), and inferior overall survival (OS, P<0.001). Multivariate analysis demonstrated that elevated serum CRP levels, age >60 years, hypoalbuminemia, and elevated lactate dehydrogenase levels were independent adverse predictors of OS. Based on these four independent predictors, we constructed a new prognostic model that identified 4 groups with varying OS: group 1, no adverse factors; group 2, 1 factor; group 3, 2 factors; and group 4, 3 or 4 factors (P<0.001). The novel prognostic model was found to be superior to both the IPI in discriminating patients with different outcomes in the IPI low-risk group and the KPI in distinguishing between the low- and intermediate-low-risk groups, the intermediate-low- and high-intermediate-risk groups, and the high-intermediate- and high-risk groups. Our results suggest that pretreatment serum CRP levels represent an independent predictor of clinical outcome for patients with ENKTL. The prognostic value of the new prognostic model is superior to both IPI and KPI.

Serum C-Reactive Protein (CRP) as a Simple and Independent Prognostic Factor in Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type

PubMed Central

Xia, Yi; Huang, Jia-Jia; Huang, Hui-Qiang; Xia, Zhong-Jun; Lin, Tong-Yu; Li, Su; Cai, Xiu-Yu; Wu-Xiao, Zhi-Jun; Jiang, Wen-Qi

2013-01-01

Background C-reactive protein (CRP) is a biomarker of the inflammatory response, and it shows significant prognostic value for several types of solid tumors. The prognostic significance of CRP for lymphoma has not been fully examined. We evaluated the prognostic role of baseline serum CRP levels in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTL). Methods We retrospectively analyzed 185 patients with newly diagnosed ENKTL. The prognostic value of the serum CRP level was evaluated for the low-CRP group (CRP≤10 mg/L) versus the high-CRP group (CRP>10 mg/L). The prognostic value of the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI) were evaluated and compared with the newly developed prognostic model. Results Patients in the high-CRP group tended to display increased adverse clinical characteristics, lower rates of complete remission (P<0.001), inferior progression-free survival (PFS, P = 0.001), and inferior overall survival (OS, P<0.001). Multivariate analysis demonstrated that elevated serum CRP levels, age >60 years, hypoalbuminemia, and elevated lactate dehydrogenase levels were independent adverse predictors of OS. Based on these four independent predictors, we constructed a new prognostic model that identified 4 groups with varying OS: group 1, no adverse factors; group 2, 1 factor; group 3, 2 factors; and group 4, 3 or 4 factors (P<0.001). The novel prognostic model was found to be superior to both the IPI in discriminating patients with different outcomes in the IPI low-risk group and the KPI in distinguishing between the low- and intermediate-low-risk groups, the intermediate-low- and high-intermediate-risk groups, and the high-intermediate- and high-risk groups. Conclusions Our results suggest that pretreatment serum CRP levels represent an independent predictor of clinical outcome for patients with ENKTL. The prognostic value of the new prognostic model is superior to both IPI and KPI. PMID:23724031

miR-188-5p inhibits tumour growth and metastasis in prostate cancer by repressing LAPTM4B expression.

PubMed

Zhang, Hongtuan; Qi, Shiyong; Zhang, Tao; Wang, Andi; Liu, Ranlu; Guo, Jia; Wang, Yuzhuo; Xu, Yong

2015-03-20

Elucidation of the molecular targets and pathways regulated by the tumour-suppressive miRNAs can shed light on the oncogenic and metastatic processes in prostate cancer (PCa). Using miRNA profiling analysis, we find that miR-188-5p was significantly down-regulated in metastatic PCa. Down-regulation of miR-188-5p is an independent prognostic factor for poor overall and biochemical recurrence-free survival. Restoration of miR-188-5p in PCa cells (PC-3 and LNCaP) significantly suppresses proliferation, migration and invasion in vitro and inhibits tumour growth and metastasis in vivo. We also find overexpression of miR-188-5p in PC-3 cells can significantly enhance the cells' chemosensitivity to adriamycin. LAPTM4B is subsequently identified as a direct target of miR-188-5p in PCa, and is found to be significantly over-expressed in PCa. Knockdown of LAPTM4B phenotypically copies miR-188-5p-induced phenotypes, whereas ectopic expression of LAPTM4B reverses the effects of miR-188-5p. We also find that restoration of miR-188-5p can inhibit the PI3K/AKT signaling pathway via the suppression of LAPTM4B. Taken together, this is the first report unveils that miR-188-5p acts as a tumour suppressor in PCa and may therefore serve as a useful therapeutic target for the development of new anticancer therapy.

Different definitions of CpG island methylator phenotype and outcomes of colorectal cancer: a systematic review.

PubMed

Jia, Min; Gao, Xu; Zhang, Yan; Hoffmeister, Michael; Brenner, Hermann

2016-01-01

Contradictory results were reported for the prognostic role of CpG island methylator phenotype (CIMP) among colorectal cancer (CRC) patients. Differences in the definitions of CIMP were the most common explanation for these discrepancies. The aim of this systematic review was to give an overview of the published studies on CRC prognosis according to the different definitions of CIMP. A systematic literature search was performed in MEDLINE and ISI Web of Science for articles published until 3 April 2015. Data extraction included information about the study population, the definition of CIMP, and investigated outcomes. Thirty-six studies were included in this systematic review. Among them, 30 studies reported the association of CIMP and CRC prognosis and 11 studies reported the association of CIMP with survival after CRC therapy. Overall, 16 different definitions of CIMP were identified. The majority of studies reported a poorer prognosis for patients with CIMP-positive (CIMP+)/CIMP-high (CIMP-H) CRC than with CIMP-negative (CIMP-)/CIMP-low (CIMP-L) CRC. Inconsistent results or varying effect strengths could not be explained by different CIMP definitions used. No consistent variation in response to specific therapies according to CIMP status was found. Comparative analyses of different CIMP panels in the same large study populations are needed to further clarify the role of CIMP definitions and to find out how methylation information can best be used to predict CRC prognosis and response to specific CRC therapies.

Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier.

PubMed

Martins, Filipe C; Santiago, Ines de; Trinh, Anne; Xian, Jian; Guo, Anne; Sayal, Karen; Jimenez-Linan, Mercedes; Deen, Suha; Driver, Kristy; Mack, Marie; Aslop, Jennifer; Pharoah, Paul D; Markowetz, Florian; Brenton, James D

2014-12-17

TP53 and BRCA1/2 mutations are the main drivers in high-grade serous ovarian carcinoma (HGSOC). We hypothesise that combining tissue phenotypes from image analysis of tumour sections with genomic profiles could reveal other significant driver events. Automatic estimates of stromal content combined with genomic analysis of TCGA HGSOC tumours show that stroma strongly biases estimates of PTEN expression. Tumour-specific PTEN expression was tested in two independent cohorts using tissue microarrays containing 521 cases of HGSOC. PTEN loss or downregulation occurred in 77% of the first cohort by immunofluorescence and 52% of the validation group by immunohistochemistry, and is associated with worse survival in a multivariate Cox-regression model adjusted for study site, age, stage and grade. Reanalysis of TCGA data shows that hemizygous loss of PTEN is common (36%) and expression of PTEN and expression of androgen receptor are positively associated. Low androgen receptor expression was associated with reduced survival in data from TCGA and immunohistochemical analysis of the first cohort. PTEN loss is a common event in HGSOC and defines a subgroup with significantly worse prognosis, suggesting the rational use of drugs to target PI3K and androgen receptor pathways for HGSOC. This work shows that integrative approaches combining tissue phenotypes from images with genomic analysis can resolve confounding effects of tissue heterogeneity and should be used to identify new drivers in other cancers.

Radiomics: there is more than meets the eye in medical imaging (Conference Presentation)

NASA Astrophysics Data System (ADS)

Aerts, Hugo

2016-03-01

Imaging-based techniques have traditionally been restricted to the diagnosis of cancer and staging of cancer. But technological advances are moving imaging modalities into the heart of patient care. Radiomics uses imaging assays to develop biomarkers which complement those derived from biopsies. The ultimate goal of radiomics is to improve personalized medicine strategies by allowing clinicians to monitor disease in real time as patients move through treatment. Several studies in different cancer types have demonstrated that radiomic biomarkers have strong prognostic performance, and are associated with underlying mutation and gene-expression patterns. In this talk, Dr. Aerts will discuss recent developments from his lab and collaborators performing research at the intersection of radiology and bioinformatics. Also, he will discuss recent work of building a computational image analysis system to extract a rich radiomics set and use these features to build prognostic radiomics signatures. The presentation will conclude with a discussion of future work on building integrative systems incorporating both molecular and phenotypic data to improve cancer therapies.

Systematic review of current prognostication systems for primary gastrointestinal stromal tumors.

PubMed

Khoo, Chun Yuet; Chai, Xun; Quek, Richard; Teo, Melissa C C; Goh, Brian K P

2018-04-01

The advent of tyrosine kinase inhibitors as adjuvant therapy has revolutionized the management of GIST and emphasized the need for accurate prognostication systems. Numerous prognostication systems have been proposed for GIST but at present it remains unknown which system is superior. The present systematic review aims to summarize current prognostication systems for primary treatment-naive GIST. A literature review of the Pubmed and Embase databases was performed to identify all published articles in English, from the 1st January 2002 to 28th Feb 2017, reporting on clinical prognostication systems of GIST. Twenty-three articles on GIST prognostication systems were included. These systems were classified as categorical systems, which stratify patients into risk groups, or continuous systems, which provide an individualized form of risk assessment. There were 16 categorical systems in total. There were 4 modifications of the National Institute of Health (NIH) system, 2 modifications of Armed Forces Institute of Pathology (AFIP) criteria and 3 modifications of Joensuu (modified NIH) criteria. Of the 7 continuous systems, there were 3 prognostic nomograms, 3 mathematical models and 1 prognostic heat/contour maps. Tumor size, location and mitotic count remain the main variables used in these systems. Numerous prognostication systems have been proposed for the risk stratification of GISTs. The most widely used systems today are the NIH, Joensuu modified NIH, AFIP and the Memorial Sloan Kettering Cancer Center nomogram. More validation and comparison studies are required to determine the optimal prognostication system for GIST. Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Prognostics of Proton Exchange Membrane Fuel Cells stack using an ensemble of constraints based connectionist networks

NASA Astrophysics Data System (ADS)

Javed, Kamran; Gouriveau, Rafael; Zerhouni, Noureddine; Hissel, Daniel

2016-08-01

Proton Exchange Membrane Fuel Cell (PEMFC) is considered the most versatile among available fuel cell technologies, which qualify for diverse applications. However, the large-scale industrial deployment of PEMFCs is limited due to their short life span and high exploitation costs. Therefore, ensuring fuel cell service for a long duration is of vital importance, which has led to Prognostics and Health Management of fuel cells. More precisely, prognostics of PEMFC is major area of focus nowadays, which aims at identifying degradation of PEMFC stack at early stages and estimating its Remaining Useful Life (RUL) for life cycle management. This paper presents a data-driven approach for prognostics of PEMFC stack using an ensemble of constraint based Summation Wavelet- Extreme Learning Machine (SW-ELM) models. This development aim at improving the robustness and applicability of prognostics of PEMFC for an online application, with limited learning data. The proposed approach is applied to real data from two different PEMFC stacks and compared with ensembles of well known connectionist algorithms. The results comparison on long-term prognostics of both PEMFC stacks validates our proposition.

High-throughput discovery of novel developmental phenotypes

PubMed Central

Dickinson, Mary E.; Flenniken, Ann M.; Ji, Xiao; Teboul, Lydia; Wong, Michael D.; White, Jacqueline K.; Meehan, Terrence F.; Weninger, Wolfgang J.; Westerberg, Henrik; Adissu, Hibret; Baker, Candice N.; Bower, Lynette; Brown, James M.; Caddle, L. Brianna; Chiani, Francesco; Clary, Dave; Cleak, James; Daly, Mark J.; Denegre, James M.; Doe, Brendan; Dolan, Mary E.; Edie, Sarah M.; Fuchs, Helmut; Gailus-Durner, Valerie; Galli, Antonella; Gambadoro, Alessia; Gallegos, Juan; Guo, Shiying; Horner, Neil R.; Hsu, Chih-wei; Johnson, Sara J.; Kalaga, Sowmya; Keith, Lance C.; Lanoue, Louise; Lawson, Thomas N.; Lek, Monkol; Mark, Manuel; Marschall, Susan; Mason, Jeremy; McElwee, Melissa L.; Newbigging, Susan; Nutter, Lauryl M.J.; Peterson, Kevin A.; Ramirez-Solis, Ramiro; Rowland, Douglas J.; Ryder, Edward; Samocha, Kaitlin E.; Seavitt, John R.; Selloum, Mohammed; Szoke-Kovacs, Zsombor; Tamura, Masaru; Trainor, Amanda G; Tudose, Ilinca; Wakana, Shigeharu; Warren, Jonathan; Wendling, Olivia; West, David B.; Wong, Leeyean; Yoshiki, Atsushi; MacArthur, Daniel G.; Tocchini-Valentini, Glauco P.; Gao, Xiang; Flicek, Paul; Bradley, Allan; Skarnes, William C.; Justice, Monica J.; Parkinson, Helen E.; Moore, Mark; Wells, Sara; Braun, Robert E.; Svenson, Karen L.; de Angelis, Martin Hrabe; Herault, Yann; Mohun, Tim; Mallon, Ann-Marie; Henkelman, R. Mark; Brown, Steve D.M.; Adams, David J.; Lloyd, K.C. Kent; McKerlie, Colin; Beaudet, Arthur L.; Bucan, Maja; Murray, Stephen A.

2016-01-01

Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 lethal genes during the production of the first 1751 unique gene knockouts. Using a standardised phenotyping platform that incorporates high-resolution 3D imaging, we identified novel phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes identified in our screen, thus providing a novel dataset that facilitates prioritization and validation of mutations identified in clinical sequencing efforts. PMID:27626380

A contemporary review of management and prognostic factors of upper tract urothelial carcinoma.

PubMed

Leow, Jeffrey J; Orsola, Anna; Chang, Steven L; Bellmunt, Joaquim

2015-04-01

Upper tract urothelial carcinoma (UTUC) accounts for <5% of all urothelial cancers. Although the main treatment is radical nephroureterectomy (NU), oncologic outcomes are not comparable to lower tract urothelial cancers. Identifying prognostic factors can help guide management and potentially improve outcomes. This article systematically reviews current literature on prognostic factors and management options for UTUC. A comprehensive literature search was performed to identify all studies examining prognostic factors and management options for UTUC. The search included the Medline, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to November 2014. An updated systematic review was performed. Preoperative prognostic factors for UTUC patients include age, race, performance status, obesity, smoking status, elevated fibrinogen levels, hydronephrosis, tumor size, multi-focality, location, clinical grade and previous/synchronous bladder cancer. Postoperative variables include tumor stage/grade, multifocality, nodal involvement, lympho-vascular invasion, initial ureteral location, necrosis, sessile architecture, variant histologies and presence of tissue ALDH1 and SOX2. Curative treatment of choice is NU, with lymphadenectomy conferring survival benefits. Minimally invasive surgery has equivalent oncologic and better peri-operative outcomes compared to open surgery. Conservative therapy includes adjuvant BCG and intravesical mitomycin C. Two randomized trials investigating postoperative instillation of mitomycin C suggest bladder recurrence benefits. Adjuvant chemo-radiotherapy may be useful for patients with advanced T3/4 and/or N+ disease. Gold-standard treatment for UTUC remains NU, increasingly performed using minimally invasive surgery. Nomograms including pre- and post-operative variables can aid prognostication and guide further therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Distributed Prognostics based on Structural Model Decomposition

NASA Technical Reports Server (NTRS)

Daigle, Matthew J.; Bregon, Anibal; Roychoudhury, I.

2014-01-01

Within systems health management, prognostics focuses on predicting the remaining useful life of a system. In the model-based prognostics paradigm, physics-based models are constructed that describe the operation of a system and how it fails. Such approaches consist of an estimation phase, in which the health state of the system is first identified, and a prediction phase, in which the health state is projected forward in time to determine the end of life. Centralized solutions to these problems are often computationally expensive, do not scale well as the size of the system grows, and introduce a single point of failure. In this paper, we propose a novel distributed model-based prognostics scheme that formally describes how to decompose both the estimation and prediction problems into independent local subproblems whose solutions may be easily composed into a global solution. The decomposition of the prognostics problem is achieved through structural decomposition of the underlying models. The decomposition algorithm creates from the global system model a set of local submodels suitable for prognostics. Independent local estimation and prediction problems are formed based on these local submodels, resulting in a scalable distributed prognostics approach that allows the local subproblems to be solved in parallel, thus offering increases in computational efficiency. Using a centrifugal pump as a case study, we perform a number of simulation-based experiments to demonstrate the distributed approach, compare the performance with a centralized approach, and establish its scalability. Index Terms-model-based prognostics, distributed prognostics, structural model decomposition ABBREVIATIONS

The neuropathological basis to the functional role of microglia/macrophages in gliomas.

PubMed

Schiffer, Davide; Mellai, Marta; Bovio, Enrica; Annovazzi, Laura

2017-09-01

The paper wants to be a tracking shot of the main recent acquisitions on the function and significance of microglia/macrophages in gliomas. The observations have been principally carried out on in vitro cultures and on tumor transplants in animals. Contrary to what is deduced from microglia in non-neoplastic pathologic conditions of central nervous system (CNS), most conclusions indicate that microglia acts favoring tumor proliferation through an immunosuppression induced by glioma cells. By immunohistochemistry, different microglia phenotypes are recognized in gliomas, from ramified microglia to frank macrophagic aspect. One wonders whether the functional conclusions drawn from many microglia studies, but not in conditions of human pathology, apply to all the phenotypes recognizable in them. It is difficult to verify in human pathology a prognostic significance of microglia. Only CD163-positive microglia/macrophages inversely correlate with glioma patients' survival, whereas the total number of microglia does not change with the malignancy grade.

EMT and EGFR in CTCs cytokeratin negative non-metastatic breast cancer

PubMed Central

Alvarez-Cubero, Maria J.; Nadal, Rosa; Sanchez-Rovira, Pedro; Salido, Marta; Rodríguez, María; García-Puche, Jose L.; Delgado-Rodriguez, Miguel; Solé, Francisco; García, Maria A.; Perán, Macarena; Rosell, Rafael; Marchal, Juan A.; Lorente, Jose A.

2014-01-01

Circulating tumor cells (CTCs) are frequently associated with epithelialmesenchymal transition (EMT). The objective of this study was to detect EMT phenotype through Vimentin (VIM) and Slug expression in cytokeratin (CK)-negative CTCs in non-metastatic breast cancer patients and to determine the importance of EGFR in the EMT phenomenon. In CK-negative CTCs samples, both VIM and Slug markers were co-expressed in the most of patients. Among patients EGFR+, half of them were positive for these EMT markers. Furthermore, after a systemic treatment 68% of patients switched from CK- to CK+ CTCs. In our experimental model we found that activation of EGFR signaling by its ligand on MCF-7 cells is sufficient to increase EMT phenotypes, to inhibit apoptotic events and to induce the loss of CK expression. The simultaneous detection of both EGFR and EMT markers in CTCs may improve prognostic or predictive information in patients with operable breast cancer. PMID:25277187

Transitions in Prognostic Awareness Among Terminally Ill Cancer Patients in Their Last 6 Months of Life Examined by Multi-State Markov Modeling.

PubMed

Hsiu Chen, Chen; Wen, Fur-Hsing; Hou, Ming-Mo; Hsieh, Chia-Hsun; Chou, Wen-Chi; Chen, Jen-Shi; Chang, Wen-Cheng; Tang, Siew Tzuh

2017-09-01

Developing accurate prognostic awareness, a cornerstone of preference-based end-of-life (EOL) care decision-making, is a dynamic process involving more prognostic-awareness states than knowing or not knowing. Understanding the transition probabilities and time spent in each prognostic-awareness state can help clinicians identify trigger points for facilitating transitions toward accurate prognostic awareness. We examined transition probabilities in distinct prognostic-awareness states between consecutive time points in 247 cancer patients' last 6 months and estimated the time spent in each state. Prognostic awareness was categorized into four states: (a) unknown and not wanting to know, state 1; (b) unknown but wanting to know, state 2; (c) inaccurate awareness, state 3; and (d) accurate awareness, state 4. Transitional probabilities were examined by multistate Markov modeling. Initially, 59.5% of patients had accurate prognostic awareness, whereas the probabilities of being in states 1-3 were 8.1%, 17.4%, and 15.0%, respectively. Patients' prognostic awareness generally remained unchanged (probabilities of remaining in the same state: 45.5%-92.9%). If prognostic awareness changed, it tended to shift toward higher prognostic-awareness states (probabilities of shifting to state 4 were 23.2%-36.6% for patients initially in states 1-3, followed by probabilities of shifting to state 3 for those in states 1 and 2 [9.8%-10.1%]). Patients were estimated to spend 1.29, 0.42, 0.68, and 3.61 months in states 1-4, respectively, in their last 6 months. Terminally ill cancer patients' prognostic awareness generally remained unchanged, with a tendency to become more aware of their prognosis. Health care professionals should facilitate patients' transitions toward accurate prognostic awareness in a timely manner to promote preference-based EOL decisions. Terminally ill Taiwanese cancer patients' prognostic awareness generally remained stable, with a tendency toward developing higher states of awareness. Health care professionals should appropriately assess patients' readiness for prognostic information and respect patients' reluctance to confront their poor prognosis if they are not ready to know, but sensitively coach them to cultivate their accurate prognostic awareness, provide desired and understandable prognostic information for those who are ready to know, and give direct and honest prognostic information to clarify any misunderstandings for those with inaccurate awareness, thus ensuring that they develop accurate and realistic prognostic knowledge in time to make end-of-life care decisions. © AlphaMed Press 2017.

The prognostic significance of circulating serum amyloid A and CXC chemokine ligand 4 in osteosarcoma.

PubMed

Flores, Ricardo J; Kelly, Aaron J; Li, Yiting; Chen, Xiang; McGee, Colin; Krailo, Mark; Barkauskas, Donald A; Hicks, John; Man, Tsz-Kwong

2017-12-01

Osteosarcoma (OS) is the most common pediatric bone cancer.  Despite advances in treatment regimens, the survival rate remains 60-70%.  There is an urgent need to identify prognostic biomarkers, so that targeted therapies can be developed to improve the outcome. Our laboratory has previously identified that circulating serum amyloid A (SAA) and CXC chemokine ligand 4 (CXCL4) are upregulated in patients with OS.  In this study, we tested if they could be used as prognostic biomarkers.  We used enzyme-linked immunosorbent assays to measure their concentrations in serum samples (n = 233) and immunohistochemistry to examine their expressions in primary tumors (n = 37).  Prognostic significance of the serum concentrations and tumor expressions of the biomarkers was then evaluated. Patients with "high SAA" and "low CXCL4" circulating levels at diagnosis significantly correlated with a worse outcome (HR = 1.68, P = 0.014), which was independent of the metastatic status.  These patients also exhibited a significantly higher rate of poor histologic response to chemotherapy.  Furthermore, low tumor expression of CXCL4 correlated with poor survival (HR = 3.57, P = 0.005). Our results demonstrate that circulating SAA and CXCL4 may serve as prognostic biomarkers in OS.  Targeting CXCL4 has been reported, suggesting that it may be exploited as a therapeutic target in OS. © 2017 Wiley Periodicals, Inc.

The Prognostic Significance of Circulating Serum Amyloid A and CXC Chemokine Ligand 4 in Osteosarcoma

PubMed Central

Flores, Ricardo J.; Kelly, Aaron J.; Li, Yiting; Chen, Xiang; McGee, Colin; Krailo, Mark; Barkauskas, Donald A.; Hicks, John; Man, Tsz-Kwong

2017-01-01

BACKGROUND Osteosarcoma is the most common pediatric bone cancer. Despite advances in treatment regimens, the survival rate remains 60–70%. There is an urgent need to identify prognostic biomarkers, so that targeted therapies can be developed to improve the outcome. PROCEDURE Our lab has previously identified that circulating Serum Amyloid A (SAA) and CXC Chemokine Ligand 4 (CXCL4) are upregulated in patients with osteosarcoma. In this study, we tested if they could be used as prognostic biomarkers. We used ELISAs to measure their concentrations in serum samples (n = 233), and immunohistochemistry to examine expressions in primary tumors (n = 37). Prognostic significance of the serum concentrations and tumor expressions of the biomarkers was then evaluated. RESULTS Patients with “High SAA” and “Low CXCL4” circulating levels at diagnosis significantly correlated with a worse outcome (HR = 1.68, p = 0.014), which was independent of the metastatic status. These patients also exhibited a significantly higher rate of poor histological response to chemotherapy. Furthermore, low tumor expression of CXCL4 correlated with poor survival (HR = 3.57, p = 0.005). CONCLUSIONS Our results demonstrate that circulating SAA and CXCL4 may serve as prognostic biomarkers in osteosarcoma. Targeting CXCL4 has been reported, suggesting that it may be exploited as a therapeutic target in osteosarcoma. PMID:28544777

TU-CD-BRB-04: Automated Radiomic Features Complement the Prognostic Value of VASARI in the TCGA-GBM Dataset

DOE Office of Scientific and Technical Information (OSTI.GOV)

Velazquez, E Rios; Narayan, V; Grossmann, P

2015-06-15

Purpose: To compare the complementary prognostic value of automated Radiomic features to that of radiologist-annotated VASARI features in TCGA-GBM MRI dataset. Methods: For 96 GBM patients, pre-operative MRI images were obtained from The Cancer Imaging Archive. The abnormal tumor bulks were manually defined on post-contrast T1w images. The contrast-enhancing and necrotic regions were segmented using FAST. From these sub-volumes and the total abnormal tumor bulk, a set of Radiomic features quantifying phenotypic differences based on the tumor intensity, shape and texture, were extracted from the post-contrast T1w images. Minimum-redundancy-maximum-relevance (MRMR) was used to identify the most informative Radiomic, VASARI andmore » combined Radiomic-VASARI features in 70% of the dataset (training-set). Multivariate Cox-proportional hazards models were evaluated in 30% of the dataset (validation-set) using the C-index for OS. A bootstrap procedure was used to assess significance while comparing the C-Indices of the different models. Results: Overall, the Radiomic features showed a moderate correlation with the radiologist-annotated VASARI features (r = −0.37 – 0.49); however that correlation was stronger for the Tumor Diameter and Proportion of Necrosis VASARI features (r = −0.71 – 0.69). After MRMR feature selection, the best-performing Radiomic, VASARI, and Radiomic-VASARI Cox-PH models showed a validation C-index of 0.56 (p = NS), 0.58 (p = NS) and 0.65 (p = 0.01), respectively. The combined Radiomic-VASARI model C-index was significantly higher than that obtained from either the Radiomic or VASARI model alone (p = <0.001). Conclusion: Quantitative volumetric and textural Radiomic features complement the qualitative and semi-quantitative annotated VASARI feature set. The prognostic value of informative qualitative VASARI features such as Eloquent Brain and Multifocality is increased with the addition of quantitative volumetric and textural features from the contrast-enhancing and necrotic tumor regions. These results should be further evaluated in larger validation cohorts.« less

Diffuse myogenin expression by immunohistochemistry is an independent marker of poor survival in pediatric rhabdomyosarcoma: a tissue microarray study of 71 primary tumors including correlation with molecular phenotype.

PubMed

Heerema-McKenney, Amy; Wijnaendts, Liliane C D; Pulliam, Joseph F; Lopez-Terrada, Dolores; McKenney, Jesse K; Zhu, Shirley; Montgomery, Kelli; Mitchell, Janet; Marinelli, Robert J; Hart, Augustinus A M; van de Rijn, Matt; Linn, Sabine C

2008-10-01

The pathologic classification of rhabdomyosarcoma (RMS) into embryonal or alveolar subtype is an important prognostic factor guiding the therapeutic protocol chosen for an individual patient. Unfortunately, this classification is not always straightforward, and the diagnostic criteria are controversial in a subset of cases. Ancillary studies are used to aid in the classification, but their potential use as independent prognostic factors is rarely studied. The aim of this study is to identify immunohistochemical markers of potential prognostic significance in pediatric RMS and to correlate their expression with PAX-3/FKHR and PAX-7/FKHR fusion status. A single tissue microarray containing 71 paraffin-embedded pediatric RMSs was immunostained with antibodies against p53, bcl-2, Ki-67, CD44, myogenin, and MyoD1. The tissue microarray and whole paraffin blocks were studied for PAX-3/FKHR and PAX-7/FKHR gene fusions by fluorescence in situ hybridization and reverse transcription-polymerase chain reaction. Clinical follow-up data were available for each patient. Immunohistochemical staining results and translocation status were correlated with recurrence-free interval (RFI) and overall survival (OS) using the Kaplan-Meier method, the log-rank test, and Cox proportional hazard regression. The minimum clinical follow-up interval was 24 months (median follow-up=57 mo). On univariable analysis, immunohistochemical expression of myogenin, bcl-2, and identification of a gene fusion were associated with decreased 5-year RFI and 10-year OS (myogenin RFI P=0.0028, OS P=0.0021; bcl-2 RFI P=0.037, OS P=0.032; gene fusion RFI P=0.0001, OS P=0.0058). After adjustment for Intergroup Rhabdomyosarcoma Study-TNM stage, tumor site, age, tumor histology, and translocation status by multivariable analysis, only myogenin retained an independent association with RFI (P=0.034) and OS (P=0.0069). In this retrospective analysis, diffuse immunohistochemical reactivity for myogenin in RMS correlates with decreased RFI and OS, independent of histologic subtype, translocation status, tumor site, or stage.

Technical Needs for Prototypic Prognostic Technique Demonstration for Advanced Small Modular Reactor Passive Components

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meyer, Ryan M.; Coble, Jamie B.; Hirt, Evelyn H.

2013-05-17

This report identifies a number of requirements for prognostics health management of passive systems in AdvSMRs, documents technical gaps in establishing a prototypical prognostic methodology for this purpose, and describes a preliminary research plan for addressing these technical gaps. AdvSMRs span multiple concepts; therefore a technology- and design-neutral approach is taken, with the focus being on characteristics that are likely to be common to all or several AdvSMR concepts. An evaluation of available literature is used to identify proposed concepts for AdvSMRs along with likely operational characteristics. Available operating experience of advanced reactors is used in identifying passive components thatmore » may be subject to degradation, materials likely to be used for these components, and potential modes of degradation of these components. This information helps in assessing measurement needs for PHM systems, as well as defining functional requirements of PHM systems. An assessment of current state-of-the-art approaches to measurements, sensors and instrumentation, diagnostics and prognostics is also documented. This state-of-the-art evaluation, combined with the requirements, may be used to identify technical gaps and research needs in the development, evaluation, and deployment of PHM systems for AdvSMRs. A preliminary research plan to address high-priority research needs for the deployment of PHM systems to AdvSMRs is described, with the objective being the demonstration of prototypic prognostics technology for passive components in AdvSMRs. Greater efficiency in achieving this objective can be gained through judicious selection of materials and degradation modes that are relevant to proposed AdvSMR concepts, and for which significant knowledge already exists. These selections were made based on multiple constraints including the analysis performed in this document, ready access to laboratory-scale facilities for materials testing and measurement, and potential synergies with other national laboratory and university partners.« less

Patient Characteristics, Treatment Patterns and Prognostic Factors in Squamous Cell Bladder Cancer.

PubMed

Zahoor, Haris; Elson, Paul; Stephenson, Andrew; Haber, Georges-Pascal; Kaouk, Jihad; Fergany, Amr; Lee, Byron; Koshkin, Vadim; Ornstein, Moshe; Gilligan, Timothy; Garcia, Jorge A; Rini, Brian; Grivas, Petros

2018-04-01

Squamous cell carcinoma (SCC) is an uncommon histologic subtype of bladder cancer with limited data on treatment patterns, outcomes, and prognostic factors. "Real world" information might inform decision-making, prognostic estimates, and clinical trial designs. A retrospective review of patients with tissue-confirmed bladder SCC treated at Cleveland Clinic from 2007 to 2016 was performed. Data on patient characteristics, treatment patterns, and clinical follow-up were extracted. Univariate analysis was used to identify predictors of overall survival (OS), recurrence-free survival (RFS) and time to recurrence. Of 58 identified patients, 42 had complete data available. Median age at diagnosis was 67 years (range, 37-90). Hematuria was the most common (71%) presenting symptom; 32 patients had pure SCC and 10 predominant/extensive squamous differentiation without major differences noted in clinicopathologic variables or outcomes among those 2 groups. Overall, 35 patients underwent cystectomy with 5 receiving neoadjuvant and 1 adjuvant chemotherapy, whereas 3 had chemotherapy for recurrent disease. Of patients with cystectomy, most had locally advanced disease (75% pT3/4, 35% pN+). Overall, 10 patients progressed and 14 died; median OS was not reached. The 2-year estimated OS, RFS, and cumulative incidence of recurrence were 61% ± 9%, 50% ± 9%, and 32% ± 9%, respectively. Hydronephrosis, older age (70 years or older), lymphovascular invasion, nodal metastases, and advanced T stage were associated with 1 or more poor outcomes. In patients with resectable bladder SCC, radical cystectomy remains the main treatment modality. The role of perioperative chemotherapy remains unclear. The identified prognostic factors might be helpful for prognostication, treatment discussion, and trial eligibility/stratification. Copyright © 2017 Elsevier Inc. All rights reserved.

[Upper gastrointestinal bleeding: usefulness of prognostic scores].

PubMed

Badel, S; Dorta, G; Carron, P-N

2011-08-24

Upper gastrointestinal bleeding is a potentially serious event, usually requiring urgent endoscopic treatment. Better stratification of the risk of complication or death could optimize management and improve patient outcomes, while ensuring adequate resource allocation. Several prognostic scores have been developed, in order to identify high risk patients, who require immediate treatment, and patients at low risk for whom endoscopy may be delayed. An ideal prognostic score should be accurate, simple, reproducible, and prospectively validated in different populations. Published scores meet these requirements only partially, and thus can only be used as part of an integrative diagnostic and therapeutic process.

Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma.

PubMed

Mendrzyk, Frank; Radlwimmer, Bernhard; Joos, Stefan; Kokocinski, Felix; Benner, Axel; Stange, Daniel E; Neben, Kai; Fiegler, Heike; Carter, Nigel P; Reifenberger, Guido; Korshunov, Andrey; Lichter, Peter

2005-12-01

Medulloblastoma is the most common malignant brain tumor in children. Despite multimodal aggressive treatment, nearly half of the patients die as a result of this tumor. Identification of molecular markers for prognosis and development of novel pathogenesis-based therapies depends crucially on a better understanding of medulloblastoma pathomechanisms. We performed genome-wide analysis of DNA copy number imbalances in 47 medulloblastomas using comparative genomic hybridization to large insert DNA microarrays (matrix-CGH). The expression of selected candidate genes identified by matrix-CGH was analyzed immunohistochemically on tissue microarrays representing medulloblastomas from 189 clinically well-documented patients. To identify novel prognostic markers, genomic findings and protein expression data were correlated to patient survival. Matrix-CGH analysis revealed frequent DNA copy number alterations of several novel candidate regions. Among these, gains at 17q23.2-qter (P < .01) and losses at 17p13.1 to 17p13.3 (P = .04) were significantly correlated to poor prognosis. Within 17q23.2-qter and 7q21.2, two of the most frequently gained chromosomal regions, confined amplicons were identified that contained the PPM1D and CDK6 genes, respectively. Immunohistochemistry revealed strong expression of PPM1D in 148 (88%) of 168 and CDK6 in 50 (30%) of 169 medulloblastomas. Overexpression of CDK6 correlated significantly with poor prognosis (P < .01) and represented an independent prognostic marker of overall survival on multivariate analysis (P = .02). We identified CDK6 as a novel molecular marker that can be determined by immunohistochemistry on routinely processed tissue specimens and may facilitate the prognostic assessment of medulloblastoma patients. Furthermore, increased protein-levels of PPM1D and CDK6 may link the TP53 and RB1 tumor suppressor pathways to medulloblastoma pathomechanisms.

Childhood CBCL Bipolar Profile and Adolescent/Young Adult Personality Disorders: A 9-year Follow-up

PubMed Central

Halperin, Jeffrey M.; Rucklidge, Julia J.; Powers, Robyn L.; Miller, Carlin J.; Newcorn, Jeffrey H.

2010-01-01

Background To assess the late adolescent psychiatric outcomes associated with a positive Child Behavior Checklist – Juvenile Bipolar Disorder Phenotype (CBCL-JBD) in children diagnosed with ADHD and followed over a 9-year period. Methods Parents of 152 children diagnosed as ADHD (ages 7–11 years) completed the CBCL. Ninety of these parents completed it again 9 years later as part of a comprehensive evaluation of Axis I and II diagnoses as assessed using semi-structured interviews. As previously proposed, the CBCL-JBD phenotype was defined as T-scores of 70 or greater on the Attention Problems, Aggression, and Anxiety/Depression subscales. Results The CBCL-JBD phenotype was found in 31% of those followed but only 4.9% of the sample continued to meet the phenotype criteria at follow up. Only two of the sample developed Bipolar Disorder by late adolescence and only one of those had the CBCL-JBD profile in childhood. The proxy did not predict any Axis I disorders. However, the CBCL-JBD proxy was highly predictive of later personality disorders. Limitations Only a subgroup of the original childhood sample was followed. Given this sample was confined to children with ADHD, it is not known whether the prediction of personality disorders from CBCL scores would generalize to a wider community or clinical population Conclusions A positive CBCL-JBD phenotype profile in childhood does not predict Axis I Disorders in late adolescence; however, it may be prognostic of the emergence of personality disorders. PMID:21056910

Aldehyde dehydrogenase 1 isoenzyme expression as a marker of cancer stem cells correlates to histopathological features in head and neck cancer: A meta-analysis

PubMed Central

Cai, Chengxuan; Kaufmann, Andreas M.; Albers, Andreas E.

2017-01-01

There is a lack of predictive biomarkers that can identify patients with head and neck squamous cell carcinoma (HNSCC) who will experience treatment failure and develop drug resistance, recurrence, and metastases. Cancer stem-like cells (CSC) were identified as a subset of cells within the tumor in a variety of solid tumors including HNSCC. CSC are considered the tumor-initiating population responsible for recurrence or metastasis and are associated with therapy resistance. This meta-analysis including fourteen studies with altogether 1258 patients updates and summarizes all relevant data on the impact of ALDH1+ CSC on the prognosis of HNSCC and its association with clinicopathological parameters. ALDH1 expression is highly correlated with tumor differentiation (G3 vs. G1+G2; odds ratio = 2.85. 95% CI: 1.72–4.73, P<0.0001) and decreased overall survival (relative risk = 1.77. 95% CI: 1.41–2.22, P<0.0001) if one out of seven studies was excluded because of heterogeneity. These findings provide insights into the understanding of more aggressive tumor phenotypes and also suggest that the prognostic value provided by HNSCC-subtyping by CSC frequency warrant further clinical investigation. PMID:29112953

Single Nucleotide Polymorphisms of Stemness Genes Predicted to Regulate RNA Splicing, microRNA and Oncogenic Signaling are Associated with Prostate Cancer Survival.

PubMed

Freedman, Jennifer A; Wang, Yanru; Li, Xuechan; Liu, Hongliang; Moorman, Patricia G; George, Daniel J; Lee, Norman H; Hyslop, Terry; Wei, Qingyi; Patierno, Steven R

2018-05-03

Prostate cancer is a clinically and molecularly heterogeneous disease, with variation in outcomes only partially predicted by grade and stage. Additional tools to distinguish indolent from aggressive disease are needed. Phenotypic characteristics of stemness correlate with poor cancer prognosis. Given this correlation, we identified single nucleotide polymorphisms (SNPs) of stemness-related genes and examined their associations with prostate cancer survival. SNPs within stemness-related genes were analyzed for association with overall survival of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Significant SNPs predicted to be functional were selected for linkage disequilibrium analysis and combined and stratified analyses. Identified SNPs were evaluated for association with gene expression. SNPs of CD44 (rs9666607), ABCC1 (rs35605 and rs212091) and GDF15 (rs1058587) were associated with prostate cancer survival and predicted to be functional. A role for rs9666607 of CD44 and rs35605 of ABCC1 in RNA splicing regulation, rs212091 of ABCC1 in miRNA binding site activity and rs1058587 of GDF15 in causing an amino acid change was predicted. These SNPs represent potential novel prognostic markers for overall survival of prostate cancer and support a contribution of the stemness pathway to prostate cancer patient outcome.

Diagnostic and Prognostic Models for Generator Step-Up Transformers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vivek Agarwal; Nancy J. Lybeck; Binh T. Pham

In 2014, the online monitoring (OLM) of active components project under the Light Water Reactor Sustainability program at Idaho National Laboratory (INL) focused on diagnostic and prognostic capabilities for generator step-up transformers. INL worked with subject matter experts from the Electric Power Research Institute (EPRI) to augment and revise the GSU fault signatures previously implemented in the Electric Power Research Institute’s (EPRI’s) Fleet-Wide Prognostic and Health Management (FW-PHM) Suite software. Two prognostic models were identified and implemented for GSUs in the FW-PHM Suite software. INL and EPRI demonstrated the use of prognostic capabilities for GSUs. The complete set of faultmore » signatures developed for GSUs in the Asset Fault Signature Database of the FW-PHM Suite for GSUs is presented in this report. Two prognostic models are described for paper insulation: the Chendong model for degree of polymerization, and an IEEE model that uses a loading profile to calculates life consumption based on hot spot winding temperatures. Both models are life consumption models, which are examples of type II prognostic models. Use of the models in the FW-PHM Suite was successfully demonstrated at the 2014 August Utility Working Group Meeting, Idaho Falls, Idaho, to representatives from different utilities, EPRI, and the Halden Research Project.« less

CD44 staining of cancer stem-like cells is influenced by down-regulation of CD44 variant isoforms and up-regulation of the standard CD44 isoform in the population of cells that have undergone epithelial-to-mesenchymal transition.

PubMed

Biddle, Adrian; Gammon, Luke; Fazil, Bilal; Mackenzie, Ian C

2013-01-01

CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumours, and we have previously demonstrated the existence of two different CD44(high) cancer stem-like cell populations in squamous cell carcinoma, one having undergone epithelial-to-mesenchymal transition and the other maintaining an epithelial phenotype. Alternative splicing of CD44 variant exons generates a great many isoforms, and it is not known which isoforms are expressed on the surface of the two different cancer stem-like cell phenotypes. Here, we demonstrate that cancer stem-like cells with an epithelial phenotype predominantly express isoforms containing the variant exons, whereas the cancer stem-like cells that have undergone an epithelial-to-mesenchymal transition down-regulate these variant isoforms and up-regulate expression of the standard CD44 isoform that contains no variant exons. In addition, we find that enzymatic treatments used to dissociate cells from tissue culture or fresh tumour specimens cause destruction of variant CD44 isoforms at the cell surface whereas expression of the standard CD44 isoform is preserved. This results in enrichment within the CD44(high) population of cancer stem-like cells that have undergone an epithelial-to-mesenchymal transition and depletion from the CD44(high) population of cancer stem-like cells that maintain an epithelial phenotype, and therefore greatly effects the characteristics of any cancer stem-like cell population isolated based on expression of CD44. As well as effecting the CD44(high) population, enzymatic treatment also reduces the percentage of the total epithelial cancer cell population staining CD44-positive, with potential implications for studies that aim to use CD44-positive staining as a prognostic indicator. Analyses of the properties of cancer stem-like cells are largely dependent on the ability to accurately identify and assay these populations. It is therefore critical that consideration be given to use of multiple cancer stem-like cell markers and suitable procedures for cell isolation in order that the correct populations are assayed.

Associations of circulating plasma microRNAs with age, body mass index and sex in a population-based study.

PubMed

Ameling, Sabine; Kacprowski, Tim; Chilukoti, Ravi Kumar; Malsch, Carolin; Liebscher, Volkmar; Suhre, Karsten; Pietzner, Maik; Friedrich, Nele; Homuth, Georg; Hammer, Elke; Völker, Uwe

2015-10-14

Non-cellular blood circulating microRNAs (plasma miRNAs) represent a promising source for the development of prognostic and diagnostic tools owing to their minimally invasive sampling, high stability, and simple quantification by standard techniques such as RT-qPCR. So far, the majority of association studies involving plasma miRNAs were disease-specific case-control analyses. In contrast, in the present study, plasma miRNAs were analysed in a sample of 372 individuals from a population-based cohort study, the Study of Health in Pomerania (SHIP). Quantification of miRNA levels was performed by RT-qPCR using the Exiqon Serum/Plasma Focus microRNA PCR Panel V3.M covering 179 different miRNAs. Of these, 155 were included in our analyses after quality-control. Associations between plasma miRNAs and the phenotypes age, body mass index (BMI), and sex were assessed via a two-step linear regression approach per miRNA. The first step regressed out the technical parameters and the second step determined the remaining associations between the respective plasma miRNA and the phenotypes of interest. After regressing out technical parameters and adjusting for the respective other two phenotypes, 7, 15, and 35 plasma miRNAs were significantly (q < 0.05) associated with age, BMI, and sex, respectively. Additional adjustment for the blood cell parameters identified 12 and 19 miRNAs to be significantly associated with age and BMI, respectively. Most of the BMI-associated miRNAs likely originate from liver. Sex-associated differences in miRNA levels were largely determined by differences in blood cell parameters. Thus, only 7 as compared to originally 35 sex-associated miRNAs displayed sex-specific differences after adjustment for blood cell parameters. These findings emphasize that circulating miRNAs are strongly impacted by age, BMI, and sex. Hence, these parameters should be considered as covariates in association studies based on plasma miRNA levels. The established experimental and computational workflow can now be used in future screening studies to determine associations of plasma miRNAs with defined disease phenotypes.

LincIN, a novel NF90-binding long non-coding RNA, is overexpressed in advanced breast tumors and involved in metastasis.

PubMed

Jiang, Zhengyu; Slater, Carolyn M; Zhou, Yan; Devarajan, Karthik; Ruth, Karen J; Li, Yueran; Cai, Kathy Q; Daly, Mary; Chen, Xiaowei

2017-05-30

Recent genome-wide profiling by sequencing and distinctive chromatin signatures has identified thousands of long non-coding RNA (lncRNA) species (>200 nt). LncRNAs have emerged as important regulators of gene expression, involving in both developmental and pathological processes. While altered expression of lncRNAs has been observed in breast cancer development, their roles in breast cancer progression and metastasis are still poorly understood. To identify novel breast cancer-associated lncRNA candidates, we employed a high-density SNP array-based approach to uncover intergenic lncRNA genes that are aberrantly expressed in breast cancer. We first evaluated the potential value as a breast cancer prognostic biomarker for one breast cancer-associated lncRNA, LincIN, using a breast cancer cohort retrieved from The Cancer Genome Atlas (TCGA) Data Portal. Then we characterized the role of LincIN in breast cancer progression and metastasis by in vitro invasion assay and a mouse tail vein injection metastasis model. To study the action of LincIN, we identified LincIN-interacting protein partner(s) by RNA pull-down experiments followed with protein identification by mass spectrometry. High levels of LincIN expression are frequently observed in tumors compared to adjacent normal tissues, and are strongly associated with aggressive breast cancer. Importantly, analysis of TCGA data further suggest that high expression of LincIN is associated with poor overall survival in patients with breast cancer (P = 0.044 and P = 0.011 after adjustment for age). The functional experiments demonstrate that knockdown of LincIN inhibits tumor cell migration and invasion in vitro, which is supported by the results of transcriptome analysis in the LincIN-knockdown cells. Furthermore, knockdown of LincIN diminishes lung metastasis in a mouse tail vein injection model. We also identified a LincIN-binding protein, NF90, through which overexpression of LincIN may repress p21 protein expression by inhibiting its translation, and upregulation of p21 by LincIN knockdown may be associated with less aggressive metastasis phenotypes. Our studies provide clear evidence to support LincIN as a new regulator of tumor progression-metastasis at both transcriptional and translational levels and as a promising prognostic biomarker for breast cancer.

Potential Biomarkers of Fat Loss as a Feature of Cancer Cachexia.

PubMed

Ebadi, Maryam; Mazurak, Vera C

2015-01-01

Fat loss is associated with shorter survival and reduced quality of life in cancer patients. Effective intervention for fat loss in cachexia requires identification of the condition using prognostic biomarkers for early detection and prevention of further depletion. No biomarkers of fat mass alterations have been defined for application to the neoplastic state. Several inflammatory cytokines have been implicated in mediating fat loss associated with cachexia; however, plasma levels may not relate to adipose atrophy. Zinc-α2-glycoprotein may be a local catabolic mediator within adipose tissue rather than serving as a plasma biomarker of fat loss. Plasma glycerol and leptin associate with adipose tissue atrophy and mass, respectively; however, no study has evaluated their potential as a prognostic biomarker of cachexia-associated fat loss. This review confirms the need for further studies to identify valid prognostic biomarkers to identify loss of fat based on changes in plasma levels of biomarkers.

Prognostic significance of membrane-associated mucins 1 and 4 in gastric adenocarcinoma.

PubMed

Hwang, Ilseon; Kang, Yu Na; Kim, Jin Young; DO, Young Rok; Song, Hong Suk; Park, Keon Uk

2012-08-01

Aberrant expression of mucins is likely associated with cancer biology as alterations in the expression and/or glycosylation patterns of various mucins have been noted. Expression of the mucin family in gastric cancers has been reported in numerous studies, but the results are conflicting. Therefore, we investigated the potential use of mucin (MUC)1 and 4 as prognostic markers in gastric cancer according to histological subtype. Three-hundred and sixty-five gastric adenocarcinoma patients who underwent surgical resection were selected for this study. Among the 365 gastric cancer samples tested here, 34% consisted of early gastric cancer and 66% were advanced. In terms of location, 68.7% of the cohort had intestinal-type cancer and 30.7% had diffuse-type. We constructed tissue microarrays with formalin-fixed paraffin-embedded blocks of gastric cancer and these micro-arrays were evaluated for phenotypic expression of MUC1/4 using monoclonal antibodies. Two-hundred and ninety-two patients (92.7%) were positive for MUC1 and 216 (60.5%) were positive for MUC4. MUC1 expression was not correlated with any other clinicopathological variables such as age, gender, depth of invasion, lymph node metastasis, Lauren classification or recurrence. However, loss of MUC4 expression was significantly correlated with recurrence (p=0.033). MUC4 expression was also significantly correlated with better disease-free survival (p=0.049) and particularly in the intestinal-type (p=0.018). Our present findings demonstrated that loss of MUC4 expression can be used as a prognostic marker in gastric cancer. Loss of MUC4 expression is a prognostic indicator of increased recurrence and poor disease-free survival in patients with gastric cancer.

Patients with metastatic breast cancer leading to CD4+ T cell lymphopaenia have poor outcome.

PubMed

Trédan, Olivier; Manuel, Manuarii; Clapisson, Gilles; Bachelot, Thomas; Chabaud, Sylvie; Bardin-dit-Courageot, Christine; Rigal, Chantal; Biota, Cathy; Bajard, Agathe; Pasqual, Nicolas; Blay, Jean-Yves; Caux, Christophe; Ménétrier-Caux, Christine

2013-05-01

Low lymphocyte count is a prognostic factor in cancer patients including metastatic breast cancer patients (MBC) but the relative role of each lymphocyte subtype is unclear in MBC. The impact of lymphocyte subsets was analysed in two prospective MBC patients' cohorts. Cohort A patients (n=103) were included before the first line of chemotherapy and cohort B patients (n=101) were included after at least one line of chemotherapy. Extensive phenotypic analyses were performed on fresh whole blood. Plasma cytokines levels were measured using commercially available Luminex-based multiplex kits. Prognostic value of lymphocyte subsets and circulating cytokines was analysed. In both cohorts, severe lymphopaenia (<0.7 Giga/L) correlated with poor overall survival (OS) (median OS: 6.6 months versus 21.7 months in cohort A and 4.5 versus 9 months in cohort B). CD8(+), CD19(+) and CD56(+) T cell counts had no significant prognostic value for OS. After stratification (≤0.2, [0.20-0.45], >0.45 Giga/L), CD4 lymphopaenia appeared to be correlated with poor OS in both cohorts. Furthermore, severe CD4(+) lymphopaenia (≤0.2 Giga/L) was strongly correlated with poor OS in both cohorts (1.2 months versus 24.9 months in cohort A and 5.7 versus 13.1 months in cohort B). In multivariate analysis, after stratification CD4(+) lymphopaenia appeared to be an independent prognostic factor for OS in both cohorts. CD4(+) lymphopaenia correlated with low plasmatic levels of CCL22 that might directly contribute to CD4(+) lymphopaenia. CD4(+) lymphopaenia was associated with reduced OS in MBC patients regardless of the chemotherapy line. Decreased levels of plasmatic CCL22 may contribute to CD4(+) lymphopaenia. Copyright © 2012 Elsevier Ltd. All rights reserved.

Low BRMS1 expression promotes nasopharyngeal carcinoma metastasis in vitro and in vivo and is associated with poor patient survival

PubMed Central

2012-01-01

Background Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene. This study aimed to investigate the impact of BRMS1 on metastasis in nasopharyngeal carcinoma (NPC) and to evaluate the prognostic significance of BRMS1 in NPC patients. Methods BRMS1 expression was examined in NPC cell lines using quantitative reverse transcription-polymerase chain reaction and Western blotting. NPC cells stably expressing BRMS1 were used to perform wound healing and invasion assays in vitro and a murine xenograft assay in vivo. Immunohistochemical staining was performed in 274 paraffin-embedded NPC specimens divided into a training set (n = 120) and a testing set (n = 154). Results BRMS1 expression was down-regulated in NPC cell lines. Overexpression of BRMS1 significantly reversed the metastatic phenotype of NPC cells in vitro and in vivo. Importantly, low BRMS1 expression was associated with poor distant metastasis-free survival (DMFS, P < 0.001) and poor overall survival (OS, P < 0.001) in the training set; these results were validated in the testing set and overall patient population. Cox regression analysis demonstrated that low BRMS1 expression was an independent prognostic factor for DMFS and OS in NPC. Conclusions Low expression of the metastasis suppressor BRMS1 may be an independent prognostic factor for poor prognosis in NPC patients. PMID:22931099

HOXB7 overexpression in lung cancer is a hallmark of acquired stem-like phenotype.

PubMed

Monterisi, Simona; Lo Riso, Pietro; Russo, Karin; Bertalot, Giovanni; Vecchi, Manuela; Testa, Giuseppe; Di Fiore, Pier Paolo; Bianchi, Fabrizio

2018-03-26

HOXB7 is a homeodomain (HOX) transcription factor involved in regional body patterning of invertebrates and vertebrates. We previously identified HOXB7 within a ten-gene prognostic signature for lung adenocarcinoma, where increased expression of HOXB7 was associated with poor prognosis. This raises the question of how HOXB7 overexpression can influence the metastatic behavior of lung adenocarcinoma. Here, we analyzed publicly available microarray and RNA-seq lung cancer expression datasets and found that HOXB7-overexpressing tumors are enriched in gene signatures characterizing adult and embryonic stem cells (SC), and induced pluripotent stem cells (iPSC). Experimentally, we found that HOXB7 upregulates several canonical SC/iPSC markers and sustains the expansion of a subpopulation of cells with SC characteristics, through modulation of LIN28B, an emerging cancer gene and pluripotency factor, which we discovered to be a direct target of HOXB7. We validated this new circuit by showing that HOXB7 enhances reprogramming to iPSC with comparable efficiency to LIN28B or its target c-MYC, which is a canonical reprogramming factor.

Metastatic Organotropism: An Intrinsic Property of Breast Cancer Molecular Subtypes.

PubMed

Wei, Shi; Siegal, Gene P

2017-03-01

It has long been known that some cancers have the propensity to metastasize to certain organs thus creating a nonrandom distribution of sites for distant relapse, a phenomenon known as "metastatic organotropism." Some of these examples include ovary primary to abdominal cavity, prostate primary to bone, and pancreas primary to liver. In contrast, other tumor types, such as mammary and renal cell carcinoma, can relapse in multiple organs although approximately half of advanced breast cancers metastasize to bone. On the other hand gene expression profiling studies have identified various breast cancer classes with prognostic significance. Recent studies have revealed that breast cancer subtypes differ not only in primary tumor characteristics but also in their metastatic behavior. In particular, the luminal tumors are remarkable for their significant bone-seeking phenotype; the HER2 subtype demonstrates a significant liver-homing characteristic; whereas so-called triple-negative breast cancers predispose to lung metastases. These findings suggest that this knowledge could potentially be utilized in the development of effective disease surveillance strategies in the pursuit of precision medicine, thus necessitating further investigation.

Digit-Length Ratios (2D:4D) as a Phenotypic Indicator of in Utero Androgen Exposure is Not Prognostic for Androgenic Alopecia: a Descriptive-Analytic Study of 1200 Iranian Men.

PubMed

Feily, Amir; Hosseinpoor, Masoomeh; Bakhti, Ali; Nekuyi, Mohamad; Sobhanian, Saeed; Fathinezhad, Zahra; Sahraei, Reza; Ramirez-Fort, Marigdalia K

2016-06-15

The etiology of androgenic alopecia (AGA) involves several factors, including genetics, androgens, age and nutrition. Digit-length ratio of the index and ring finger (2D:4D) is an indicator of prenatal exposure to sex hormones. There is a paucity of studies that systemically review the possible positive predictive value of 2D:4D in the development of AGA. We performed a single-site, descriptive-analytical study among a racially homogeneous population. Our results revealed that no significant association was determined between right 2D:4D and AGA severity within our entire population (P=0.384, r=0.025), however a positive correlation coefficient was identified in subjects above the age of 40. Based on the receiver operating characteristic curve analysis, 2D:4D does not predict the development of AGA. AGA is truly a multifactorial disease. Further, our findings suggest that increased in utero exposure to androgens as a fetus does not predispose men to develop AGA.

Assessment of nutritional status in cancer--the relationship between body composition and pharmacokinetics.

PubMed

Prado, Carla M M; Maia, Yara L M; Ormsbee, Michael; Sawyer, Michael B; Baracos, Vickie E

2013-10-01

Several nutritional assessment tools have been used in oncology settings to monitor nutritional status and its associated prognostic significance. Body composition is fundamental for the assessment of nutritional status. Recently, the use of accurate and precise body composition tools has significantly added to the value of nutritional assessment in this clinical setting. Computerized tomography (CT) is an example of a technique which provides state-of-the-art assessment of body composition. With use of CT images, a great variability in body composition of cancer patients has been identified even in people with identical body weight or body mass index. Severe muscle depletion (sarcopenia) has emerged as a prevalent body composition phenotype which is predictive of poor functional status, shorter time to tumor progression, shorter survival, and higher incidence of dose-limiting toxicity. Variability in body composition of cancer patients may be a source of disparities in the metabolism of cytotoxic agents. Future clinical trials investigating dose reductions in patients with sarcopenia and dose-escalating studies based on pre-treatment body composition assessment have the potential to alter cancer treatment paradigms.

Chromosome 17 alterations identify good-risk and poor-risk tumors independently of clinical factors in medulloblastoma

PubMed Central

McCabe, Martin G.; Bäcklund, L. Magnus; Leong, Hui Sun; Ichimura, Koichi; Collins, V. Peter

2011-01-01

Current risk stratification schemas for medulloblastoma, based on combinations of clinical variables and histotype, fail to accurately identify particularly good- and poor-risk tumors. Attempts have been made to improve discriminatory power by combining clinical variables with cytogenetic data. We report here a pooled analysis of all previous reports of chromosomal copy number related to survival data in medulloblastoma. We collated data from previous reports that explicitly quoted survival data and chromosomal copy number in medulloblastoma. We analyzed the relative prognostic significance of currently used clinical risk stratifiers and the chromosomal aberrations previously reported to correlate with survival. In the pooled dataset metastatic disease, incomplete tumor resection and severe anaplasia were associated with poor outcome, while young age at presentation was not prognostically significant. Of the chromosomal variables studied, isolated 17p loss and gain of 1q correlated with poor survival. Gain of 17q without associated loss of 17p showed a trend to improved outcome. The most commonly reported alteration, isodicentric chromosome 17, was not prognostically significant. Sequential multivariate models identified isolated 17p loss, isolated 17q gain, and 1q gain as independent prognostic factors. In a historical dataset, we have identified isolated 17p loss as a marker of poor outcome and 17q gain as a novel putative marker of good prognosis. Biological markers of poor-risk and good-risk tumors will be critical in stratifying treatment in future trials. Our findings should be prospectively validated independently in future clinical studies. PMID:21292688

Literature-based prediction of novel drug indications considering relationships between entities.

PubMed

Jang, Giup; Lee, Taekeon; Lee, Byung Mun; Yoon, Youngmi

2017-06-27

There have been many attempts to identify and develop new uses for existing drugs, which is known as drug repositioning. Among these efforts, text mining is an effective means of discovering novel knowledge from a large amount of literature data. We identify a gene regulation by a drug and a phenotype based on the biomedical literature. Drugs or phenotypes can activate or inhibit gene regulation. We calculate the therapeutic possibility that a drug acts on a phenotype by means of these two types of regulation. We assume that a drug treats a phenotype if the genes regulated by the phenotype are inversely correlated with the genes regulated by the drug. Based on this hypothesis, we identify drug-phenotype associations with therapeutic possibility. To validate the drug-phenotype associations predicted by our method, we make an enrichment comparison with known drug-phenotype associations. We also identify candidate drugs for drug repositioning from novel associations and thus reveal that our method is a novel approach to drug repositioning.

Application of molecular biology of differentiated thyroid cancer for clinical prognostication.

PubMed

Marotta, Vincenzo; Sciammarella, Concetta; Colao, Annamaria; Faggiano, Antongiulio

2016-11-01

Although cancer outcome results from the interplay between genetics and environment, researchers are making a great effort for applying molecular biology in the prognostication of differentiated thyroid cancer (DTC). Nevertheless, role of molecular characterisation in the prognostic setting of DTC is still nebulous. Among the most common and well-characterised genetic alterations related to DTC, including mutations of BRAF and RAS and RET rearrangements, BRAF V600E is the only mutation showing unequivocal association with clinical outcome. Unfortunately, its accuracy is strongly limited by low specificity. Recently, the introduction of next-generation sequencing techniques led to the identification of TERT promoter and TP53 mutations in DTC. These genetic abnormalities may identify a small subgroup of tumours with highly aggressive behaviour, thus improving specificity of molecular prognostication. Although knowledge of prognostic significance of TP53 mutations is still anecdotal, mutations of the TERT promoter have showed clear association with clinical outcome. Nevertheless, this genetic marker needs to be analysed according to a multigenetic model, as its prognostic effect becomes negligible when present in isolation. Given that any genetic alteration has demonstrated, taken alone, enough specificity, the co-occurrence of driving mutations is emerging as an independent genetic signature of aggressiveness, with possible future application in clinical practice. DTC prognostication may be empowered in the near future by non-tissue molecular prognosticators, including circulating BRAF V600E and miRNAs. Although promising, use of these markers needs to be refined by the technical sight, and the actual prognostic value is still yet to be validated. © 2016 Society for Endocrinology.

IgV H mutations in blastoid mantle cell lymphoma characterize a subgroup with a tendency to more favourable clinical outcome.

PubMed

Cogliatti, Sergio B; Bertoni, Francesco; Zimmermann, Dieter R; Henz, Samuel; Diss, Tim C; Ghielmini, Michele; Schmid, Ulrico

2005-07-01

Mantle cell lymphoma (MCL) is associated with a very unfavourable clinical course. This is particularly true for mantle cell lymphoma of the blastoid subtype (MCL-b). In order to define prognostic factors, we analysed the impact of immunoglobulin heavy chain variable (IgV H) gene somatic hypermutations on clinical outcome in a series of 21 cases of morphologically, phenotypically, and genotypically well-characterized MCL-b. Testing and estimation were performed using log-rank statistics and displayed on Kaplan-Meier graphs. Thirteen of 21 cases of MCL-b revealed a homology rate of > or = 99% compared to IgV H germ-line sequences in the databases and were scored as non-mutated. Eight of 21 cases (38%) of MCL-b were mutated. In MCL-b the mutation frequency was usually low and the mutation pattern was only rarely antigen-selected, in contrast to a control group of 11 cases with morphologically almost identical, but phenotypically and genotypically clearly distinguishable, diffuse large B cell lymphoma, derived, most likely, from germinal centre B cells. In our series of 21 MCL-b, positive IgV H mutational status, irrespective of varying homology thresholds, had no statistically significant prognostic impact on event-free or overall survival. However, mutated MCL-b tended to present more frequently at an earlier stage and without bone marrow involvement and to show lower rates of relapse and death, resulting in a more favourable clinical outcome. Copyright 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Glasgow Prognostic Score is a predictor of perioperative and long-term outcome in patients with only surgically treated esophageal cancer.

PubMed

Vashist, Yogesh K; Loos, Julian; Dedow, Josephine; Tachezy, Michael; Uzunoglu, Guentac; Kutup, Asad; Yekebas, Emre F; Izbicki, Jakob R

2011-04-01

Systemic inflammation (SI) plays a pivotal role in cancer. C-reactive protein (CRP) and albumin as parameters of SI form the Glasgow Prognostic Score (GPS). The purpose of the study was to evaluate the potential prognostic role of GPS in a homogeneous population of esophageal cancer (EC) patients undergoing only resection. GPS was evaluated on the basis of admission blood sample taken before surgery. Patients with a CRP < 10 mg/L and albumin > 35 g/L were allocated to GPS0 group. If only CRP was increased or albumin decreased patients were allocated to the GPS1 and patients in whom CRP was ≥10 mg/L and albumin level ≤35 g/L were classified as GPS2. GPS was correlated to clinicopathological parameters and clinical outcome. Increasing GPS significantly correlated with more aggressive tumor biology in terms of tumor size (P < 0.001), presence of regional (P = 0.01) and nonregional lymph node metastasis (P = 0.02), and higher tumor recurrence rate (P < 0.001). Furthermore, GPS was identified as an independent prognosticator of perioperative morbidity (odds ratio 1.9; P = 0.03). In addition, a gradual decrease in disease-free and overall survival was evident between the three GPS subgroups. Survival differences between the GPS groups remained apparent even after stratification of the study population to underlying tumor type and nodal status. GPS was identified as a strong prognosticator of tumor recurrence (hazard ratio 2.5; P < 0.001) and survival (hazard ratio 3.0; P < 0.001) in EC. GPS represents a strong prognosticator of perioperative morbidity and long-term outcome in resected EC patients without neoadjuvant or adjuvant treatment.

Heterogeneity of (18)F-FDG PET combined with expression of EGFR may improve the prognostic stratification of advanced oropharyngeal carcinoma.

PubMed

Wang, Hung-Ming; Cheng, Nai-Ming; Lee, Li-Yu; Fang, Yu-Hua Dean; Chang, Joseph Tung-Chieh; Tsan, Din-Li; Ng, Shu-Hang; Liao, Chun-Ta; Yang, Lan-Yan; Yen, Tzu-Chen

2016-02-01

The Ang's risk profile (based on p16, smoking and cancer stage) is a well-known prognostic factor in oropharyngeal squamous cell carcinoma (OPSCC). Whether heterogeneity in (18)F-fluorodeoxyglucose (FDG) positron emission tomographic (PET) images and epidermal growth factor receptor (EGFR) expression could provide additional information on clinical outcomes in advanced-stage OPSCC was investigated. Patients with stage III-IV OPSCC who completed primary therapy were eligible. Zone-size nonuniformity (ZSNU) extracted from pretreatment FDG PET scans was used as an index of image heterogeneity. EGFR and p16 expression were examined by immunohistochemistry. Disease-specific survival (DSS) and overall survival (OS) served as outcome measures. Kaplan-Meier estimates and Cox proportional hazards regression models were used for survival analysis. A bootstrap resampling technique was applied to investigate the stability of outcomes. Finally, a recursive partitioning analysis (RPA)-based model was constructed. A total of 113 patients were included, of which 28 were p16-positive. Multivariate analysis identified the Ang's profile, EGFR and ZSNU as independent predictors of both DSS and OS. Using RPA, the three risk factors were used to devise a prognostic scoring system that successfully predicted DSS in both p16-positive and -negative cases. The c-statistic of the prognostic index for DSS was 0.81, a value which was significantly superior to both AJCC stage (0.60) and the Ang's risk profile (0.68). In patients showing an Ang's high-risk profile (N = 77), the use of our scoring system clearly identified three distinct prognostic subgroups. It was concluded that a novel index may improve the prognostic stratification of patients with advanced-stage OPSCC. © 2015 UICC.

Macroscopic appearance of Type IV and giant Type III is a high risk for a poor prognosis in pathological stage II/III advanced gastric cancer with postoperative adjuvant chemotherapy

PubMed Central

Yamashita, Keishi; Ema, Akira; Hosoda, Kei; Mieno, Hiroaki; Moriya, Hiromitsu; Katada, Natsuya; Watanabe, Masahiko

2017-01-01

AIM To evaluate whether a high risk macroscopic appearance (Type IV and giant Type III) is associated with a dismal prognosis after curative surgery, because its prognostic relevance remains elusive in pathological stage II/III (pStage II/III) gastric cancer. METHODS One hundred and seventy-two advanced gastric cancer (defined as pT2 or beyond) patients with pStage II/III who underwent curative surgery plus adjuvant S1 chemotherapy were evaluated, and the prognostic relevance of a high-risk macroscopic appearance was examined. RESULTS Advanced gastric cancers with a high-risk macroscopic appearance were retrospectively identified by preoperative recorded images. A high-risk macroscopic appearance showed a significantly worse relapse free survival (RFS) (35.7%) and overall survival (OS) (34%) than an average risk appearance (P = 0.0003 and P < 0.0001, respectively). A high-risk macroscopic appearance was significantly associated with the 13th Japanese Gastric Cancer Association (JGCA) pT (P = 0.01), but not with the 13th JGCA pN. On univariate analysis for RFS and OS, prognostic factors included 13th JGCA pStage (P < 0.0001) and other clinicopathological factors including macroscopic appearance. A multivariate Cox proportional hazards model for univariate prognostic factors identified high-risk macroscopic appearance (P = 0.036, HR = 2.29 for RFS and P = 0.021, HR = 2.74 for OS) as an independent prognostic indicator. CONCLUSION A high-risk macroscopic appearance was associated with a poor prognosis, and it could be a prognostic factor independent of 13th JGCA stage in pStage II/III advanced gastric cancer. PMID:28451064

Serum prognostic biomarkers in head and neck cancer patients.

PubMed

Lin, Ho-Sheng; Siddiq, Fauzia; Talwar, Harvinder S; Chen, Wei; Voichita, Calin; Draghici, Sorin; Jeyapalan, Gerald; Chatterjee, Madhumita; Fribley, Andrew; Yoo, George H; Sethi, Seema; Kim, Harold; Sukari, Ammar; Folbe, Adam J; Tainsky, Michael A

2014-08-01

A reliable estimate of survival is important as it may impact treatment choice. The objective of this study is to identify serum autoantibody biomarkers that can be used to improve prognostication for patients affected with head and neck squamous cell carcinoma (HNSCC). Prospective cohort study. A panel of 130 serum biomarkers, previously selected for cancer detection using microarray-based serological profiling and specialized bioinformatics, were evaluated for their potential as prognostic biomarkers in a cohort of 119 HNSCC patients followed for up to 12.7 years. A biomarker was considered positive if its reactivity to the particular patient's serum was greater than one standard deviation above the mean reactivity to sera from the other 118 patients, using a leave-one-out cross-validation model. Survival curves were estimated according to the Kaplan-Meier method, and statistically significant differences in survival were examined using the log rank test. Independent prognostic biomarkers were identified following analysis using multivariate Cox proportional hazards models. Poor overall survival was associated with African Americans (hazard ratio [HR] for death = 2.61; 95% confidence interval [CI]: 1.58-4.33; P = .000), advanced stage (HR = 2.79; 95% CI: 1.40-5.57; P = .004), and recurrent disease (HR = 6.66; 95% CI: 2.54-17.44; P = .000). On multivariable Cox analysis adjusted for covariates (race and stage), six of the 130 markers evaluated were found to be independent prognosticators of overall survival. The results shown here are promising and demonstrate the potential use of serum biomarkers for prognostication in HNSCC patients. Further clinical trials to include larger samples of patients across multiple centers may be warranted. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

Serum Prognostic Biomarkers in Head and Neck Cancer Patients

PubMed Central

Lin, Ho-Sheng; Siddiq, Fauzia; Talwar, Harvinder S.; Chen, Wei; Voichita, Calin; Draghici, Sorin; Jeyapalan, Gerald; Chatterjee, Madhumita; Fribley, Andrew; Yoo, George H.; Sethi, Seema; Kim, Harold; Sukari, Ammar; Folbe, Adam J.; Tainsky, Michael A.

2014-01-01

Objectives/Hypothesis A reliable estimate of survival is important as it may impact treatment choice. The objective of this study is to identify serum autoantibody biomarkers that can be used to improve prognostication for patients affected with head and neck squamous cell carcinoma (HNSCC). Study Design Prospective cohort study. Methods A panel of 130 serum biomarkers, previously selected for cancer detection using microarray-based serological profiling and specialized bioinformatics, were evaluated for their potential as prognostic biomarkers in a cohort of 119 HNSCC patients followed for up to 12.7 years. A biomarker was considered positive if its reactivity to the particular patient’s serum was greater than one standard deviation above the mean reactivity to sera from the other 118 patients, using a leave-one-out cross-validation model. Survival curves were estimated according to the Kaplan-Meier method, and statistically significant differences in survival were examined using the log rank test. Independent prognostic biomarkers were identified following analysis using multivariate Cox proportional hazards models. Results Poor overall survival was associated with African Americans (hazard ratio [HR] for death =2.61; 95% confidence interval [CI]: 1.58–4.33; P =.000), advanced stage (HR =2.79; 95% CI: 1.40–5.57; P =.004), and recurrent disease (HR =6.66; 95% CI: 2.54–17.44; P =.000). On multivariable Cox analysis adjusted for covariates (race and stage), six of the 130 markers evaluated were found to be independent prognosticators of overall survival. Conclusions The results shown here are promising and demonstrate the potential use of serum biomarkers for prognostication in HNSCC patients. Further clinical trials to include larger samples of patients across multiple centers may be warranted. PMID:24347532

A multigene predictor of metastatic outcome in early stage hormone receptor-negative and triple-negative breast cancer

PubMed Central

2010-01-01

Introduction Various multigene predictors of breast cancer clinical outcome have been commercialized, but proved to be prognostic only for hormone receptor (HR) subsets overexpressing estrogen or progesterone receptors. Hormone receptor negative (HRneg) breast cancers, particularly those lacking HER2/ErbB2 overexpression and known as triple-negative (Tneg) cases, are heterogeneous and generally aggressive breast cancer subsets in need of prognostic subclassification, since most early stage HRneg and Tneg breast cancer patients are cured with conservative treatment yet invariably receive aggressive adjuvant chemotherapy. Methods An unbiased search for genes predictive of distant metastatic relapse was undertaken using a training cohort of 199 node-negative, adjuvant treatment naïve HRneg (including 154 Tneg) breast cancer cases curated from three public microarray datasets. Prognostic gene candidates were subsequently validated using a different cohort of 75 node-negative, adjuvant naïve HRneg cases curated from three additional datasets. The HRneg/Tneg gene signature was prognostically compared with eight other previously reported gene signatures, and evaluated for cancer network associations by two commercial pathway analysis programs. Results A novel set of 14 prognostic gene candidates was identified as outcome predictors: CXCL13, CLIC5, RGS4, RPS28, RFX7, EXOC7, HAPLN1, ZNF3, SSX3, HRBL, PRRG3, ABO, PRTN3, MATN1. A composite HRneg/Tneg gene signature index proved more accurate than any individual candidate gene or other reported multigene predictors in identifying cases likely to remain free of metastatic relapse. Significant positive correlations between the HRneg/Tneg index and three independent immune-related signatures (STAT1, IFN, and IR) were observed, as were consistent negative associations between the three immune-related signatures and five other proliferation module-containing signatures (MS-14, ONCO-RS, GGI, CSR/wound and NKI-70). Network analysis identified 8 genes within the HRneg/Tneg signature as being functionally linked to immune/inflammatory chemokine regulation. Conclusions A multigene HRneg/Tneg signature linked to immune/inflammatory cytokine regulation was identified from pooled expression microarray data and shown to be superior to other reported gene signatures in predicting the metastatic outcome of early stage and conservatively managed HRneg and Tneg breast cancer. Further validation of this prognostic signature may lead to new therapeutic insights and spare many newly diagnosed breast cancer patients the need for aggressive adjuvant chemotherapy. PMID:20946665

HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer

PubMed Central

Chang, Hae Ryung; Nam, Seungyoon; Kook, Myeong-Cherl; Kim, Kyung-Tae; Liu, Xiuping; Yao, Hui; Jung, Hae Rim; Lemos, Robert; Seo, Hye Hyun; Park, Hee Seo; Gim, Youme; Hong, Dongwan; Huh, Iksoo; Kim, Young-Woo; Tan, Dongfeng; Liu, Chang-Gong; Powis, Garth; Park, Taesung; Liang, Han; Kim, Yon Hui

2016-01-01

Background Worldwide, gastric cancer (GC) is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. Objective To determine oncogenic mechanisms and novel therapeutic targets specific for GC by identifying commonly dysregulated genes from the tumours of both Asian-Pacific and Caucasian patients. Methods We generated transcriptomic profiles of 22 Caucasian GC tumours and their matched non-cancerous samples and performed an integrative analysis across different GC gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signalling pathways by RNAi and/or pharmacological inhibition. Results Hepatocyte nuclear factor-4α (HNF4α) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signalling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4α also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours. Conclusions Our results indicate that HNF4α is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKα and resides upstream of WNT signalling. HNF4α may regulate ‘metabolic switch’ characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signalling cascade represents a potentially targetable pathway for drug development. PMID:25410163

Prognostic significance of highly sulfated chondroitin sulfates in ovarian cancer defined by the single chain antibody GD3A11.

PubMed

van der Steen, Sophieke C H A; van Tilborg, Angela A G; Vallen, Myrtille J E; Bulten, Johan; van Kuppevelt, Toin H; Massuger, Leon F A G

2016-03-01

The extracellular matrix (ECM) of ovarian cancer may provide a number of potential biomarkers. Chondroitin sulfate (CS), a class of sulfated polysaccharides, is abundantly present in the ECM of ovarian cancer. Structural alterations of CS chains (i.e. sulfation pattern) have been demonstrated to play a role in cancer development and progression. In this study we investigate the potential of highly sulfated CS as a biomarker in ovarian cancer using the single chain antibody GD3A11 selected by the phage display technology. The specificity of the antibody was determined by an indirect ELISA. GD3A11 epitope expression was assessed by immunohistochemistry in healthy organs, benign and malignant ovarian tumors (N=359) and correlated to clinical parameters. The CHST15 gene, responsible for the biosynthesis of highly sulfated CS was evaluated for mutation and methylation status. The GD3A11 epitope was minimally expressed in normal organs. Intense expression was observed in the ECM of different ovarian cancer subtypes, in contrast to benign ovarian tumors. Expression was independent of tumor grade, FIGO stage, and the use chemotherapy. For the aggressive ovarian cancer phenotype, intense expression was identified as an independent predictor for poor prognosis. CHST15 gene analysis showed no mutations nor an altered methylation status. Specific highly sulfated CS motifs expressed in the tumoral ECM hold biomarker potential in ovarian cancer patients. These matrix motifs constitute a novel class of biomarkers with prognostic significance and may be instrumental for innovative diagnostic and therapeutic applications (e.g. targeted therapy) in management of ovarian cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Inflammation-based prognostic score and number of lymph node metastases are independent prognostic factors in esophageal squamous cell carcinoma.

PubMed

Kobayashi, Takashi; Teruya, Masanori; Kishiki, Tomokazu; Kaneko, Susumu; Endo, Daisuke; Takenaka, Yoshiharu; Miki, Kenji; Kobayashi, Kaoru; Morita, Koji

2010-08-01

Few studies have investigated whether the Glasgow Prognostic Score (GPS), an inflammation-based prognostic score, is useful for postoperative prognosis of esophageal squamous cell carcinoma. GPS was calculated on the basis of admission data as follows: patients with elevated C-reactive protein level (>10 mg/l) and hypoalbuminemia (<35 g/l) were assigned to GPS2. Patients with one or no abnormal value were assigned to GPS1 or GPS0. A new scoring system was constructed using independent prognostic variables and was evaluated on whether it could be used to dictate the choice of clinical options. 65 patients with esophageal squamous cell carcinoma were enrolled. GPS and the number of lymph node metastases were found to be independent prognostic variables. The scoring system comprising GPS and the number of lymph node metastases was found to be effective in the prediction of a long-term outcome (p < 0.0001). Preoperative GPS may be useful for postoperative prognosis of patients with esophageal squamous cell carcinoma. GPS and the number of lymph node metastases could be used to identify a subgroup of patients with esophageal squamous cell carcinoma who are eligible for radical resection but show poor prognosis.

Practical prognostic index for patients with metastatic recurrent breast cancer: retrospective analysis of 2,322 patients from the GEICAM Spanish El Alamo Register.

PubMed

Puente, Javier; López-Tarruella, Sara; Ruiz, Amparo; Lluch, Ana; Pastor, Miguel; Alba, Emilio; de la Haba, Juan; Ramos, Manuel; Cirera, Luis; Antón, Antonio; Llombart, Antoni; Plazaola, Arrate; Fernández-Aramburo, Antonio; Sastre, Javier; Díaz-Rubio, Eduardo; Martin, Miguel

2010-07-01

Women with recurrent metastatic breast cancer from a Spanish hospital registry (El Alamo, GEICAM) were analyzed in order to identify the most helpful prognostic factors to predict survival and to ultimately construct a practical prognostic index. The inclusion criteria covered women patients diagnosed with operable invasive breast cancer who had metastatic recurrence between 1990 and 1997 in GEICAM hospitals. Patients with stage IV breast cancer at initial diagnosis or with isolated loco-regional recurrence were excluded from this analysis. Data from 2,322 patients with recurrent breast cancer after primary treatment (surgery, radiation and systemic adjuvant treatment) were used to construct the prognostic index. The prognostic index score for each individual patient was calculated by totalling up the scores of each independent variable. The maximum score obtainable was 26.1. Nine-hundred and sixty-two patients who had complete data for all the variables were used in the computation of the prognostic index score. We were able to stratify them into three prognostic groups based on the prognostic index score: 322 patients in the good risk group (score < or =13.5), 308 patients in the intermediate risk group (score 13.51-15.60) and 332 patients in the poor risk group (score > or =15.61). The median survivals for these groups were 3.69, 2.27 and 1.02 years, respectively (P < 0.0001). In conclusion, risk scores are extraordinarily valuable tools, highly recommendable in the clinical practice.

Diagnosis-Specific Prognostic Factors, Indexes, and Treatment Outcomes for Patients With Newly Diagnosed Brain Metastases: A Multi-Institutional Analysis of 4,259 Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sperduto, Paul W., E-mail: psperduto@mropa.co; Chao, Samuel T.; Sneed, Penny K.

2010-07-01

Purpose: Controversy endures regarding the optimal treatment of patients with brain metastases (BMs). Debate persists, despite many randomized trials, perhaps because BM patients are a heterogeneous population. The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis-Specific Graded Prognostic Assessment [DS-GPA]). Methods and Materials: A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11 institutions. After exclusion of the patients with recurrent BMs or incomplete data, 4,259 patients with newly diagnosed BMs remained eligible for analysis. Univariate and multivariate analyses of the prognostic factors and outcomes bymore » primary site and treatment were performed. The significant prognostic factors were determined and used to define the DS-GPA prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment. Results: The significant prognostic factors varied by diagnosis. For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. For melanoma and renal cell cancer, the significant prognostic factors were Karnofsky performance status and the number of BMs. For breast and gastrointestinal cancer, the only significant prognostic factor was the Karnofsky performance status. Two new DS-GPA indexes were thus designed for breast/gastrointestinal cancer and melanoma/renal cell carcinoma. The median survival by GPA score, diagnosis, and treatment were determined. Conclusion: The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non-small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and statistical separation between the groups was confirmed. These data should be considered in the design of future randomized trials and in clinical decision-making.« less

Prognostic factors in patients with metastatic spinal cord compression secondary to melanoma: a systematic review.

PubMed

Hadden, Nicholas J; McIntosh, Jerome R D; Jay, Samuel; Whittaker, Paula J

2018-02-01

Melanoma is one of the most common primary tumours associated with metastatic spinal cord compression (MSCC). The aim of this review is to identify prognostic factors specifically for MSCC secondary to melanoma. A systematic search of literature was performed in MEDLINE, Embase and the Cochrane Library to identify studies reporting prognostic factors for patients with MSCC secondary to melanoma. Two studies, involving a total of 39 patients, fulfilled the inclusion criteria. The variables associated with increased survival were receiving postoperative radiotherapy, receiving chemotherapy, perioperative lactate dehydrogenase level less than or equal to 8.0 µkat/l, preoperative haemoglobin level more than 11.5 mg/dl, an interval of 4 or more years between melanoma diagnosis and skeletal metastasis, absence of further skeletal metastases, absence of visceral metastases, Eastern Cooperative Oncology Group Performance Status of 2 or less, two or fewer involved vertebrae, being ambulatory preradiotherapy and an interval of more than 7 days between developing motor deficits and radiotherapy. The variables associated with good functional outcome were slow development of motor dysfunction, good performance status and being ambulatory before radiotherapy. The most important prognostic factors for survival are Eastern Cooperative Oncology Group Performance Status of 2 or less and absence of visceral metastases. There is a lack of studies looking specifically at prognostic factors for patients with MSCC secondary to melanoma, and the number of patients involved in the existing studies is small.

A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways

PubMed Central

Huang, Tianzhi; Alvarez, Angel A.; Pangeni, Rajendra P.; M. Horbinski, Craig; Lu, Songjian; Kim, Sung-Hak; James, C. David; J. Raizer, Jeffery; A. Kessler, John; Brenann, Cameron W.; Sulman, Erik P.; Finocchiaro, Gaetano; Tan, Ming; Nishikawa, Ryo; Lu, Xinghua; Nakano, Ichiro; Hu, Bo; Cheng, Shi-Yuan

2016-01-01

Molecularly defined subclassification is associated with phenotypic malignancy of glioblastoma (GBM). However, current understanding of the molecular basis of subclass conversion that is often involved in GBM recurrence remain rudimentary at best. Here we report that canonical Wnt signalling that is active in proneural (PN) but inactive in mesenchymal (MES) GBM, along with miR-125b and miR-20b that are expressed at high levels in PN compared with MES GBM, comprise a regulatory circuit involving TCF4-miR-125b/miR-20b-FZD6. FZD6 acts as a negative regulator of this circuit by activating CaMKII–TAK1–NLK signalling, which, in turn, attenuates Wnt pathway activity while promoting STAT3 and NF-κB signalling that are important regulators of the MES-associated phenotype. These findings are confirmed by targeting differentially enriched pathways in PN versus MES GBM that results in inhibition of distinct GBM subtypes. Correlative expressions of the components of this circuit are prognostic relevant for clinical GBM. Our findings provide insights for understanding GBM pathogenesis and for improving treatment of GBM. PMID:27698350

Identification and individualized prediction of clinical phenotypes in bipolar disorders using neurocognitive data, neuroimaging scans and machine learning.

PubMed

Wu, Mon-Ju; Mwangi, Benson; Bauer, Isabelle E; Passos, Ives C; Sanches, Marsal; Zunta-Soares, Giovana B; Meyer, Thomas D; Hasan, Khader M; Soares, Jair C

2017-01-15

Diagnosis, clinical management and research of psychiatric disorders remain subjective - largely guided by historically developed categories which may not effectively capture underlying pathophysiological mechanisms of dysfunction. Here, we report a novel approach of identifying and validating distinct and biologically meaningful clinical phenotypes of bipolar disorders using both unsupervised and supervised machine learning techniques. First, neurocognitive data were analyzed using an unsupervised machine learning approach and two distinct clinical phenotypes identified namely; phenotype I and phenotype II. Second, diffusion weighted imaging scans were pre-processed using the tract-based spatial statistics (TBSS) method and 'skeletonized' white matter fractional anisotropy (FA) and mean diffusivity (MD) maps extracted. The 'skeletonized' white matter FA and MD maps were entered into the Elastic Net machine learning algorithm to distinguish individual subjects' phenotypic labels (e.g. phenotype I vs. phenotype II). This calculation was performed to ascertain whether the identified clinical phenotypes were biologically distinct. Original neurocognitive measurements distinguished individual subjects' phenotypic labels with 94% accuracy (sensitivity=92%, specificity=97%). TBSS derived FA and MD measurements predicted individual subjects' phenotypic labels with 76% and 65% accuracy respectively. In addition, individual subjects belonging to phenotypes I and II were distinguished from healthy controls with 57% and 92% accuracy respectively. Neurocognitive task variables identified as most relevant in distinguishing phenotypic labels included; Affective Go/No-Go (AGN), Cambridge Gambling Task (CGT) coupled with inferior fronto-occipital fasciculus and callosal white matter pathways. These results suggest that there may exist two biologically distinct clinical phenotypes in bipolar disorders which can be identified from healthy controls with high accuracy and at an individual subject level. We suggest a strong clinical utility of the proposed approach in defining and validating biologically meaningful and less heterogeneous clinical sub-phenotypes of major psychiatric disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Genome-wide screen identifies a novel prognostic signature for breast cancer survival

DOE PAGES

Mao, Xuan Y.; Lee, Matthew J.; Zhu, Jeffrey; ...

2017-01-21

Large genomic datasets in combination with clinical data can be used as an unbiased tool to identify genes important in patient survival and discover potential therapeutic targets. We used a genome-wide screen to identify 587 genes significantly and robustly deregulated across four independent breast cancer (BC) datasets compared to normal breast tissue. Gene expression of 381 genes was significantly associated with relapse-free survival (RFS) in BC patients. We used a gene co-expression network approach to visualize the genetic architecture in normal breast and BCs. In normal breast tissue, co-expression cliques were identified enriched for cell cycle, gene transcription, cell adhesion,more » cytoskeletal organization and metabolism. In contrast, in BC, only two major co-expression cliques were identified enriched for cell cycle-related processes or blood vessel development, cell adhesion and mammary gland development processes. Interestingly, gene expression levels of 7 genes were found to be negatively correlated with many cell cycle related genes, highlighting these genes as potential tumor suppressors and novel therapeutic targets. A forward-conditional Cox regression analysis was used to identify a 12-gene signature associated with RFS. A prognostic scoring system was created based on the 12-gene signature. This scoring system robustly predicted BC patient RFS in 60 sampling test sets and was further validated in TCGA and METABRIC BC data. Our integrated study identified a 12-gene prognostic signature that could guide adjuvant therapy for BC patients and includes novel potential molecular targets for therapy.« less

Genome-wide screen identifies a novel prognostic signature for breast cancer survival

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mao, Xuan Y.; Lee, Matthew J.; Zhu, Jeffrey

Large genomic datasets in combination with clinical data can be used as an unbiased tool to identify genes important in patient survival and discover potential therapeutic targets. We used a genome-wide screen to identify 587 genes significantly and robustly deregulated across four independent breast cancer (BC) datasets compared to normal breast tissue. Gene expression of 381 genes was significantly associated with relapse-free survival (RFS) in BC patients. We used a gene co-expression network approach to visualize the genetic architecture in normal breast and BCs. In normal breast tissue, co-expression cliques were identified enriched for cell cycle, gene transcription, cell adhesion,more » cytoskeletal organization and metabolism. In contrast, in BC, only two major co-expression cliques were identified enriched for cell cycle-related processes or blood vessel development, cell adhesion and mammary gland development processes. Interestingly, gene expression levels of 7 genes were found to be negatively correlated with many cell cycle related genes, highlighting these genes as potential tumor suppressors and novel therapeutic targets. A forward-conditional Cox regression analysis was used to identify a 12-gene signature associated with RFS. A prognostic scoring system was created based on the 12-gene signature. This scoring system robustly predicted BC patient RFS in 60 sampling test sets and was further validated in TCGA and METABRIC BC data. Our integrated study identified a 12-gene prognostic signature that could guide adjuvant therapy for BC patients and includes novel potential molecular targets for therapy.« less

The physical phenotype of frailty for risk stratification of older medical inpatients.

PubMed

Forti, P; Maioli, F; Zagni, E; Lucassenn, T; Montanari, L; Maltoni, B; Luca Pirazzoli, G; Bianchi, G; Zoli, M

2014-12-01

To determine the usefulness of physical phenotype of frailty, cognitive impairment, and serum albumin for risk stratification of elderly medical impatients. Prospective, observational cohort study. A general internal medicine unit of a university hospital in Italy. Inpatients with an average age of 80.8 ± 7.5 yr (N = 470). Frailty was defined using the Study of Osteoporotic Fractures Index, a parsimonious version of the physical phenotype (two of the following markers: weight loss, inability to rise five times from a chair, and exhaustion). Two frailty markers from non-physical dimensions were also evaluated: cognitive impairment (Mini-Cog score < 3) and low serum albumin on ward admission (< 3,5 gr/dl). Logistic regression adjusted for preadmission and admission-related confounders was used to investigate whether the physical phenotype of frailty and the two non-physical markers were associated with ward length of stay and unfavorable discharge (death plus any other ward discharge disposition different from direct return home). Areas Under the receiver operating characteristic Curve (AUCs) and Likelihood Ratios (LRs) were used for evaluation of discriminatory ability and clinical usefulness of significant predictors. The physical phenotype of frailty was associated with both study outcomes (p < 0.010) but the association was mainly mediated by chair standing ability. Non-physical markers were associated only with unfavourable discharge (p < 0.001). All of these predictors, either alone or in combination, had poor discriminatory ability (AUCs < 0.70) and poor clinical usefulness (+LRs near 1) for the study outcomes. The physical phenotype of frailty appears of limited clinical use for risk stratification of older medical inpatients. Combination with markers from non-physical dimensions does not improve its prognostic abilities.

Molecular Analysis of BMPR2, TBX4, and KCNK3 and Genotype-Phenotype Correlations in Spanish Patients and Families With Idiopathic and Hereditary Pulmonary Arterial Hypertension.

PubMed

Navas, Paula; Tenorio, Jair; Quezada, Carlos Andrés; Barrios, Elvira; Gordo, Gema; Arias, Pedro; López Meseguer, Manuel; Santos-Lozano, Alejandro; Palomino Doza, Julian; Lapunzina, Pablo; Escribano Subías, Pilar

2016-11-01

Recent advances in genetics have led to the discovery of new genes associated with pulmonary arterial hypertension, such as TBX4 and KCNK3. The phenotype and prognosis associated with these new genes have been scarcely described and their role in the Spanish population is unknown. The aim of this study was to characterize the genetics of a Spanish cohort of patients with idiopathic and hereditary pulmonary arterial hypertension and to describe the phenotype and prognostic factors associated with BMPR2 and the new genes (KCNK3 and TBX4). A total of 165 adult patients were screened for BMPR2, KCNK3, and TBX4 mutations, 143 with idiopathic pulmonary arterial hypertension and 22 with hereditary pulmonary arterial hypertension. Baseline characteristics and survival were compared among the different subgroups and predictors of poor outcomes were analyzed. We also performed family screening. The genetic study identified a possibly associated mutation in 11.10% of the idiopathic cases (n = 16) and in 68.18% of the hereditary cases (n = 15). There were 19 mutations in BMPR2, 4 in TBX4, and 3 in KCNK3. The forms associated with TBX4 showed the highest survival rate (P < .01). Advanced functional class at diagnosis was the only factor associated with poor outcomes in the hereditary forms. In the family screening, 37.5% of relatives tested positive. The genetics of pulmonary arterial hypertension in the Spanish population may differ from other populations, with a lower proportion of BMPR2 causative mutations. In our cohort, TBX4-related forms of pulmonary arterial hypertension showed a more benign course and late diagnosis was the only predictor of adverse outcomes in the hereditary forms of the disease. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

High-content image informatics of the structural nuclear protein NuMA parses trajectories for stem/progenitor cell lineages and oncogenic transformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vega, Sebastián L.; Liu, Er; Arvind, Varun

Stem and progenitor cells that exhibit significant regenerative potential and critical roles in cancer initiation and progression remain difficult to characterize. Cell fates are determined by reciprocal signaling between the cell microenvironment and the nucleus; hence parameters derived from nuclear remodeling are ideal candidates for stem/progenitor cell characterization. Here we applied high-content, single cell analysis of nuclear shape and organization to examine stem and progenitor cells destined to distinct differentiation endpoints, yet undistinguishable by conventional methods. Nuclear descriptors defined through image informatics classified mesenchymal stem cells poised to either adipogenic or osteogenic differentiation, and oligodendrocyte precursors isolated from different regionsmore » of the brain and destined to distinct astrocyte subtypes. Nuclear descriptors also revealed early changes in stem cells after chemical oncogenesis, allowing the identification of a class of cancer-mitigating biomaterials. To capture the metrology of nuclear changes, we developed a simple and quantitative “imaging-derived” parsing index, which reflects the dynamic evolution of the high-dimensional space of nuclear organizational features. A comparative analysis of parsing outcomes via either nuclear shape or textural metrics of the nuclear structural protein NuMA indicates the nuclear shape alone is a weak phenotypic predictor. In contrast, variations in the NuMA organization parsed emergent cell phenotypes and discerned emergent stages of stem cell transformation, supporting a prognosticating role for this protein in the outcomes of nuclear functions. - Highlights: • High-content analysis of nuclear shape and organization classify stem and progenitor cells poised for distinct lineages. • Early oncogenic changes in mesenchymal stem cells (MSCs) are also detected with nuclear descriptors. • A new class of cancer-mitigating biomaterials was identified based on image informatics. • Textural metrics of the nuclear structural protein NuMA are sufficient to parse emergent cell phenotypes.« less

Controversies in Poland Syndrome: Alternative Diagnoses in Patients With Congenital Pectoral Muscle Deficiency.

PubMed

Baas, Martijn; Burger, Elise B; Sneiders, Dimitri; Galjaard, Robert-Jan H; Hovius, Steven E R; van Nieuwenhoven, Christianne A

2018-02-01

Poland syndrome was first described as a deficiency of the pectoral muscle with ipsilateral symbrachydactyly. Currently, numerous case reports describe variations of Poland syndrome in which pectoral muscle deficiency is often used as the only defining criterion. However, more syndromes can present with pectoral muscle deficiency. The aim of this review is to illustrate the diversity of the phenotypic spectrum of Poland syndrome and to create more awareness for alternative diagnoses in pectoral muscle deficiency. A systematic literature search was performed. Articles containing phenotypical descriptions of Poland syndrome were included. Data extraction included number of patients, sex, familial occurrence, and the definition of Poland syndrome used. In addition, hand deformities, thoracic deformities, and other deformities in each patient were recorded. Alternative syndrome diagnoses were identified in patients with a combination of hand, thorax, and other deformities. One hundred-and-thirty-six articles were included, describing 627 patients. Ten different definitions of Poland syndrome were utilized. In 58% of the cases, an upper extremity deformity was found and 43% of the cases had an associated deformity. Classic Poland syndrome was seen in 29%. Fifty-seven percent of the patients with a pectoral malformation, a hand malformation, and another deformity had at least 1feature that matched an alternative syndrome. Pectoral muscle hypoplasia is not distinctive for Poland syndrome alone but is also present in syndromes with other associated anomalies with a recognized genetic cause. Therefore, in patients with an atypical phenotype, we recommend considering other diagnoses and/or syndromes before diagnosing a patient with Poland syndrome. This can prevent diagnostic and prognostic errors. Differentiating Poland syndrome from the alternative diagnoses has serious consequences for the patient and their family in terms of inheritance and possible related anomalies. Copyright © 2018 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Serotonin at the Nexus of Impulsivity and Cue Reactivity in Cocaine Addiction

PubMed Central

Cunningham, Kathryn A.; Anastasio, Noelle C.

2014-01-01

Cocaine abuse and addiction remain great challenges on the public health agendas in the U.S. and the world. Increasingly sophisticated perspectives on addiction to cocaine and other drugs of abuse have evolved with concerted research efforts over the last 30 years. Relapse remains a particularly powerful clinical problem as, even upon termination of drug use and initiation of abstinence, the recidivism rates can be very high. The cycling course of cocaine intake, abstinence and relapse is tied to a multitude of behavioral and cognitive processes including impulsivity (a predisposition toward rapid unplanned reactions to stimuli without regard to the negative consequences), and cocaine cue reactivity (responsivity to cocaine-associated stimuli) cited as two key phenotypes that contribute to relapse vulnerability even years into recovery. Preclinical studies suggest that serotonin (5-hydroxytryptamine; 5-HT) neurotransmission in key neural circuits may contribute to these interlocked phenotypes well as the altered neurobiological states evoked by cocaine that precipitate relapse events. As such, 5-HT is an important target in the quest to to understand the neurobiology of relapse-predictive phenotypes, to successfully treat this complex disorder and improve diagnostic and prognostic capabilities. This review emphasizes the role of 5-HT and its receptor proteins in key addiction phenotypes and the implications of current findings to the future of therapeutics in addiction. PMID:23850573

High-throughput discovery of novel developmental phenotypes.

PubMed

Dickinson, Mary E; Flenniken, Ann M; Ji, Xiao; Teboul, Lydia; Wong, Michael D; White, Jacqueline K; Meehan, Terrence F; Weninger, Wolfgang J; Westerberg, Henrik; Adissu, Hibret; Baker, Candice N; Bower, Lynette; Brown, James M; Caddle, L Brianna; Chiani, Francesco; Clary, Dave; Cleak, James; Daly, Mark J; Denegre, James M; Doe, Brendan; Dolan, Mary E; Edie, Sarah M; Fuchs, Helmut; Gailus-Durner, Valerie; Galli, Antonella; Gambadoro, Alessia; Gallegos, Juan; Guo, Shiying; Horner, Neil R; Hsu, Chih-Wei; Johnson, Sara J; Kalaga, Sowmya; Keith, Lance C; Lanoue, Louise; Lawson, Thomas N; Lek, Monkol; Mark, Manuel; Marschall, Susan; Mason, Jeremy; McElwee, Melissa L; Newbigging, Susan; Nutter, Lauryl M J; Peterson, Kevin A; Ramirez-Solis, Ramiro; Rowland, Douglas J; Ryder, Edward; Samocha, Kaitlin E; Seavitt, John R; Selloum, Mohammed; Szoke-Kovacs, Zsombor; Tamura, Masaru; Trainor, Amanda G; Tudose, Ilinca; Wakana, Shigeharu; Warren, Jonathan; Wendling, Olivia; West, David B; Wong, Leeyean; Yoshiki, Atsushi; MacArthur, Daniel G; Tocchini-Valentini, Glauco P; Gao, Xiang; Flicek, Paul; Bradley, Allan; Skarnes, William C; Justice, Monica J; Parkinson, Helen E; Moore, Mark; Wells, Sara; Braun, Robert E; Svenson, Karen L; de Angelis, Martin Hrabe; Herault, Yann; Mohun, Tim; Mallon, Ann-Marie; Henkelman, R Mark; Brown, Steve D M; Adams, David J; Lloyd, K C Kent; McKerlie, Colin; Beaudet, Arthur L; Bućan, Maja; Murray, Stephen A

2016-09-22

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

Prognostic factors for early severity in a childhood multiple sclerosis cohort.

PubMed

Mikaeloff, Yann; Caridade, Guillaume; Assi, Saada; Suissa, Samy; Tardieu, Marc

2006-09-01

The goal was to identify prognostic factors for an early severe course in a cohort of patients with childhood-onset multiple sclerosis, for the construction of a predictive tool. The cohort consisted of 197 children from the French Kid Sclérose en Plaques neuropediatric cohort with relapsing/remitting multiple sclerosis beginning before the age of 16 years. Patients were included from 1990 to 2003. We used multivariate survival analysis (Cox model) to evaluate the prognostic value of clinical, MRI, and biological covariates at onset for the occurrence of a third attack or severe disability ("severity" outcome). The cohort was monitored for a mean of 5.5 +/- 3.6 years. The "severity" outcome was recorded for 144 patients (73%). The risk of severity was higher for girls, for a time between the first and second attacks of < 1 year, for childhood-onset multiple sclerosis MRI criteria at onset, for an absence of severe mental state changes at onset, and for a progressive course. A derived childhood-onset multiple sclerosis potential index for early severity was found to have a positive predictive value for severity of > 35% for the upper 2 quartiles. The clinical and MRI prognostic factors for early severity that were identified were used as the basis of a predictive tool, which will be validated in another cohort. This tool should make it possible to identify subgroups at risk of early severe disease and should facilitate therapeutic studies.

Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

NASA Astrophysics Data System (ADS)

Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

2015-06-01

Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

Methodological issues and recommendations for systematic reviews of prognostic studies: an example from cardiovascular disease.

PubMed

Dretzke, Janine; Ensor, Joie; Bayliss, Sue; Hodgkinson, James; Lordkipanidzé, Marie; Riley, Richard D; Fitzmaurice, David; Moore, David

2014-12-03

Prognostic factors are associated with the risk of future health outcomes in individuals with a particular health condition. The prognostic ability of such factors is increasingly being assessed in both primary research and systematic reviews. Systematic review methodology in this area is continuing to evolve, reflected in variable approaches to key methodological aspects. The aim of this article was to (i) explore and compare the methodology of systematic reviews of prognostic factors undertaken for the same clinical question, (ii) to discuss implications for review findings, and (iii) to present recommendations on what might be considered to be 'good practice' approaches. The sample was comprised of eight systematic reviews addressing the same clinical question, namely whether 'aspirin resistance' (a potential prognostic factor) has prognostic utility relative to future vascular events in patients on aspirin therapy for secondary prevention. A detailed comparison of methods around study identification, study selection, quality assessment, approaches to analysis, and reporting of findings was undertaken and the implications discussed. These were summarised into key considerations that may be transferable to future systematic reviews of prognostic factors. Across systematic reviews addressing the same clinical question, there were considerable differences in the numbers of studies identified and overlap between included studies, which could only partially be explained by different study eligibility criteria. Incomplete reporting and differences in terminology within primary studies hampered study identification and selection process across reviews. Quality assessment was highly variable and only one systematic review considered a checklist for studies of prognostic questions. There was inconsistency between reviews in approaches towards analysis, synthesis, addressing heterogeneity and reporting of results. Different methodological approaches may ultimately affect the findings and interpretation of systematic reviews of prognostic research, with implications for clinical decision-making.

Comprehensive analysis and validation of contemporary survival prognosticators in Korean patients with metastatic renal cell carcinoma treated with targeted therapy: prognostic impact of pretreatment neutrophil-to-lymphocyte ratio.

PubMed

Koo, Kyo Chul; Lee, Kwang Suk; Cho, Kang Su; Rha, Koon Ho; Hong, Sung Joon; Chung, Byung Ha

2016-06-01

In line with the era of targeted therapy (TT), an increasing number of prognosticators are becoming available for patients with metastatic renal cell carcinoma (mRCC). Here, potential prognosticators of cancer-specific survival (CSS) were identified based on the contemporary literature and were comprehensively validated in an independent cohort of patients treated for mRCC. Data were collected from 478 patients treated with TT for mRCC between January 1999 and July 2013 at a single institution. The analysis included 25 clinicopathological covariates that included both traditional and contemporary prognosticators. Multivariate Cox regression models were used to quantify the effect of covariates on CSS. Median survival from the initial diagnosis of metastasis was 24.5 (IQR, 11.5-55.7) months. There were 303 (63.4 %) cancer-specific deaths, yielding a 2-year CSS rate of 62.5 %. Low Karnofsky performance status (KPS), hypercalcemia, neutrophil-to-lymphocyte ratio (NLR), the number of metastatic sites (≥2), and the presence of brain metastases were independent adverse prognosticators of CSS. The C-index of the model was 0.78. Patients with at least one adverse prognosticator demonstrated lower 2-year CSS rates compared to those with no prognosticators (53.9 vs. 70.6 %; log rank p < 0.001). Together with traditional prognosticators such as KPS, hypercalcemia, and the number and location of metastases, the NLR was an independent predictor of CSS in patients with mRCC treated with TT. Our findings could be useful for guiding clinical decision making including stratification of patients for TT and inclusion in clinical trials.

Clinical implications of six inflammatory biomarkers as prognostic indicators in Ewing sarcoma

PubMed Central

Li, Yong-Jiang; Yang, Xi; Zhang, Wen-Biao; Yi, Cheng; Wang, Feng; Li, Ping

2017-01-01

Cancer-related systemic inflammation responses have been correlated with cancer development and progression. The prognostic significance of several inflammatory indicators, including neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), Glasgow Prognostic Score (GPS), C-reactive protein to albumin ratio (CRP/Alb ratio), lymphocyte–monocyte ratio (LMR), and neutrophil–platelet score (NPS), were found to be correlated with prognosis in several cancers. However, the prognostic role of these inflammatory biomarkers in Ewing sarcoma has not been evaluated. This study enrolled 122 Ewing patients. Receiver operating characteristic (ROC) analysis was generated to determine optimal cutoff values; areas under the curves (AUCs) were assessed to show the discriminatory ability of the biomarkers; Kaplan–Meier analysis was conducted to plot the survival curves; and Cox multivariate survival analysis was performed to identify independent prognostic factors. The optimal cutoff values of CRP/Alb ratio, NLR, PLR, and LMR were 0.225, 2.38, 131, and 4.41, respectively. CRP/Alb ratio had a significantly larger AUC than NLR, PLR, LMR, and NPS. Higher levels of CRP/Alb ratio (hazard ratio [HR] 2.41, P=0.005), GPS (HR 2.27, P=0.006), NLR (HR 2.07, P=0.013), and PLR (HR 1.85, P=0.032) were significantly correlated with poor prognosis. As the biomarkers had internal correlations, only the CRP/Alb ratio was involved in the multivariate Cox analysis and remained an independent prognostic indicator. The study demonstrated that CRP/Alb ratio, GPS, and NLR were effective prognostic indicators for patients with Ewing sarcoma, and the CRP/Alb ratio was the most robust prognostic indicator with a discriminatory ability superior to that of the other indicators; however, PLR, LMR, and NPS may not be suitable as prognostic indicators in Ewing sarcoma. PMID:29033609

Myositis autoantibodies

PubMed Central

Casciola-Rosen, Livia; Mammen, Andrew L.

2013-01-01

Purpose of review To review recent advances in our understanding of autoantibodies associated with dermatomyositis and the autoimmune necrotizing myopathies. Recent findings Autoantibodies preferentially associated with dermatomyositis include those recognizing Mi-2, MDA5, TIF1 γ, and NXP-2. Each of these is associated with a distinct clinical phenotype. Autoantibodies found in patients with autoimmune necrotizing myopathies recognize SRP and HMG-CoA reductase. The latter are found in patients with statin-associated autoimmune muscle disease. Summary As these are helpful both diagnostically and prognostically, a rheumatologist should be familiar with autoantibodies found in patients with dermatomyositis and the autoimmune necrotizing myopathies. PMID:22955022

Identifying Treatment Effect Modifiers in the STarT Back Trial: A Secondary Analysis.

PubMed

Beneciuk, Jason M; Hill, Jonathan C; Campbell, Paul; Afolabi, Ebenezer; George, Steven Z; Dunn, Kate M; Foster, Nadine E

2017-01-01

Identification of patient characteristics influencing treatment outcomes is a top low back pain (LBP) research priority. Results from the STarT Back trial support the effectiveness of prognostic stratified care for LBP compared with current best care, however, patient characteristics associated with treatment response have not yet been explored. The purpose of this secondary analysis was to identify treatment effect modifiers within the STarT Back trial at 4-month follow-up (n = 688). Treatment response was dichotomized using back-specific physical disability measured using the Roland-Morris Disability Questionnaire (≥7). Candidate modifiers were identified using previous literature and evaluated using logistic regression with statistical interaction terms to provide preliminary evidence of treatment effect modification. Socioeconomic status (SES) was identified as an effect modifier for disability outcomes (odds ratio [OR] = 1.71, P = .028). High SES patients receiving prognostic stratified care were 2.5 times less likely to have a poor outcome compared with low SES patients receiving best current care (OR = .40, P = .006). Education level (OR = 1.33, P = .109) and number of pain medications (OR = .64, P = .140) met our criteria for effect modification with weaker evidence (.20 > P ≥ .05). These findings provide preliminary evidence for SES, education, and number of pain medications as treatment effect modifiers of prognostic stratified care delivered in the STarT Back Trial. This analysis provides preliminary exploratory findings about the characteristics of patients who might least likely benefit from targeted treatment using prognostic stratified care for LBP. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Distinct Molecular Phenotypes of Direct vs Indirect ARDS in Single-Center and Multicenter Studies

PubMed Central

Janz, David R.; Bernard, Gordon R.; May, Addison K.; Kangelaris, Kirsten N.; Matthay, Michael A.; Ware, Lorraine B.

2015-01-01

BACKGROUND: ARDS is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (eg, nonpulmonary sepsis); however, this hypothesis has not been well studied in humans. METHODS: We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single-center study of 100 patients with ARDS and severe sepsis and in a secondary analysis of 853 patients with ARDS drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts. RESULTS: In both studies, patients with direct ARDS had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2) than those with indirect ARDS. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, patients with direct ARDS also had lower levels of von Willebrand factor antigen and IL-6 and IL-8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS. CONCLUSIONS: Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct and indirect ARDS, respectively. PMID:26033126

B-cell subset alterations and correlated factors in HIV-1 infection.

PubMed

Pensieroso, Simone; Galli, Laura; Nozza, Silvia; Ruffin, Nicolas; Castagna, Antonella; Tambussi, Giuseppe; Hejdeman, Bo; Misciagna, Donatella; Riva, Agostino; Malnati, Mauro; Chiodi, Francesca; Scarlatti, Gabriella

2013-05-15

During HIV-1 infection, the development, phenotype, and functionality of B cells are impaired. Transitional B cells and aberrant B-cell populations arise in blood, whereas a declined percentage of resting memory B cells is detected. Our study aimed at pinpointing the demographic, immunological, and viral factors driving these pathological findings, and the role of antiretroviral therapy in reverting these alterations. B-cell phenotype and correlating factors were evaluated. Variations in B-cell subsets were evaluated by flow cytometry in HIV-1-infected individuals naive to therapy, elite controllers, and patients treated with antiretroviral drugs (virological control or failure). Multivariable analysis was performed to identify variables independently associated with the B-cell alterations. Significant differences were observed among patients' groups in relation to all B-cell subsets. Resting memory B cells were preserved in patients naive to therapy and elite controllers, but reduced in treated patients. Individuals naive to therapy and experiencing multidrug failure, as well as elite controllers, had significantly higher levels of activated memory B cells compared to healthy controls. In the multivariate analysis, plasma viral load and nadir CD4 T cells independently correlated with major B-cell alterations. Coinfection with hepatitis C but not hepatitis B virus also showed an impact on specific B-cell subsets. Successful protracted antiretroviral treatment led to normalization of all B-cell subsets with exception of resting memory B cells. Our results indicate that viremia and nadir CD4 T cells are important prognostic markers of B-cell perturbations and provide evidence that resting memory B-cell depletion during chronic infection is not reverted upon successful antiretroviral therapy.

miR-188-5p inhibits tumour growth and metastasis in prostate cancer by repressing LAPTM4B expression

PubMed Central

Zhang, Hongtuan; Qi, Shiyong; Zhang, Tao; Wang, Andi; Liu, Ranlu; Guo, Jia; Wang, Yuzhuo; Xu, Yong

2015-01-01

Elucidation of the molecular targets and pathways regulated by the tumour-suppressive miRNAs can shed light on the oncogenic and metastatic processes in prostate cancer (PCa). Using miRNA profiling analysis, we find that miR-188-5p was significantly down-regulated in metastatic PCa. Down-regulation of miR-188-5p is an independent prognostic factor for poor overall and biochemical recurrence-free survival. Restoration of miR-188-5p in PCa cells (PC-3 and LNCaP) significantly suppresses proliferation, migration and invasion in vitro and inhibits tumour growth and metastasis in vivo. We also find overexpression of miR-188-5p in PC-3 cells can significantly enhance the cells' chemosensitivity to adriamycin. LAPTM4B is subsequently identified as a direct target of miR-188-5p in PCa, and is found to be significantly over-expressed in PCa. Knockdown of LAPTM4B phenotypically copies miR-188-5p-induced phenotypes, whereas ectopic expression of LAPTM4B reverses the effects of miR-188-5p. We also find that restoration of miR-188-5p can inhibit the PI3K/AKT signaling pathway via the suppression of LAPTM4B. Taken together, this is the first report unveils that miR-188-5p acts as a tumour suppressor in PCa and may therefore serve as a useful therapeutic target for the development of new anticancer therapy. PMID:25714029

Recent advances in understanding idiopathic pulmonary fibrosis

PubMed Central

Daccord, Cécile; Maher, Toby M.

2016-01-01

Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs. Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF. PMID:27303645

MR Imaging in Hypertrophic Cardiomyopathy: From Magnet to Bedside.

PubMed

Bogaert, Jan; Olivotto, Iacopo

2014-11-01

Hypertrophic cardiomyopathy ( HCM hypertrophic cardiomyopathy ), the most common genetically transmitted cardiac disorder, has been the focus of extensive research over the past 50 years. HCM hypertrophic cardiomyopathy is a multifaceted disease with highly heterogeneous genetic background, phenotypic expression, clinical presentation, and long-term outcome. Though most patients have an indolent course with a life expectancy comparable to that of the general population, early diagnosis and accurate risk profiling are essential to identify the sizeable subset at increased risk of sudden cardiac death or disease progression and heart failure-related complications, requiring aggressive management options. Imaging has a central role in the diagnosis and prognostic assessment of HCM hypertrophic cardiomyopathy patients, as well as screening of potentially affected family members. In this context, magnetic resonance (MR) imaging has recently emerged as an ideal complement to transthoracic echocardiography. Its multiparametric approach, fusing spatial, contrast, and temporal resolution, provides the clinician with detailed characterization of the HCM hypertrophic cardiomyopathy phenotype and assessment of its functional consequences including causes and site of dynamic obstruction, presence and extent of myocardial perfusion abnormalities, and fibrosis. Moreover, MR is key in differentiating HCM hypertrophic cardiomyopathy from "phenocopies"-that is, hearts with similar morphology but profoundly different etiology, such as amyloid or Anderson-Fabry disease. Long term, the incremental information provided by MR is relevant to planning of septal reduction therapies, identification of the early stages of end-stage progression, and stratification of arrhythmic risk. The aim of this review is to depict the increasingly important role of MR imaging in relation to the complexity of HCM hypertrophic cardiomyopathy , highlighting its role in clinical decision making.

Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies.

PubMed

Calfee, Carolyn S; Janz, David R; Bernard, Gordon R; May, Addison K; Kangelaris, Kirsten N; Matthay, Michael A; Ware, Lorraine B

2015-06-01

ARDS is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (eg, nonpulmonary sepsis); however, this hypothesis has not been well studied in humans. We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single-center study of 100 patients with ARDS and severe sepsis and in a secondary analysis of 853 patients with ARDS drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts. In both studies, patients with direct ARDS had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2) than those with indirect ARDS. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, patients with direct ARDS also had lower levels of von Willebrand factor antigen and IL-6 and IL-8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS. Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct and indirect ARDS, respectively.

MIDAS: Mining differentially activated subpaths of KEGG pathways from multi-class RNA-seq data.

PubMed

Lee, Sangseon; Park, Youngjune; Kim, Sun

2017-07-15

Pathway based analysis of high throughput transcriptome data is a widely used approach to investigate biological mechanisms. Since a pathway consists of multiple functions, the recent approach is to determine condition specific sub-pathways or subpaths. However, there are several challenges. First, few existing methods utilize explicit gene expression information from RNA-seq. More importantly, subpath activity is usually an average of statistical scores, e.g., correlations, of edges in a candidate subpath, which fails to reflect gene expression quantity information. In addition, none of existing methods can handle multiple phenotypes. To address these technical problems, we designed and implemented an algorithm, MIDAS, that determines condition specific subpaths, each of which has different activities across multiple phenotypes. MIDAS utilizes gene expression quantity information fully and the network centrality information to determine condition specific subpaths. To test performance of our tool, we used TCGA breast cancer RNA-seq gene expression profiles with five molecular subtypes. 36 differentially activate subpaths were determined. The utility of our method, MIDAS, was demonstrated in four ways. All 36 subpaths are well supported by the literature information. Subsequently, we showed that these subpaths had a good discriminant power for five cancer subtype classification and also had a prognostic power in terms of survival analysis. Finally, in a performance comparison of MIDAS to a recent subpath prediction method, PATHOME, our method identified more subpaths and much more genes that are well supported by the literature information. http://biohealth.snu.ac.kr/software/MIDAS/. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Joint System Prognostics For Increased Efficiency And Risk Mitigation In Advanced Nuclear Reactor Instrumentation and Control

DOE Office of Scientific and Technical Information (OSTI.GOV)

Donald D. Dudenhoeffer; Tuan Q. Tran; Ronald L. Boring

2006-08-01

The science of prognostics is analogous to a doctor who, based on a set of symptoms and patient tests, assesses a probable cause, the risk to the patient, and a course of action for recovery. While traditional prognostics research has focused on the aspect of hydraulic and mechanical systems and associated failures, this project will take a joint view in focusing not only on the digital I&C aspect of reliability and risk, but also on the risks associated with the human element. Model development will not only include an approximation of the control system physical degradation but also on humanmore » performance degradation. Thus the goal of the prognostic system is to evaluate control room operation; to identify and potentially take action when performance degradation reduces plant efficiency, reliability or safety.« less

Integrated genomic analyses identify KDM1A's role in cell proliferation via modulating E2F signaling activity and associate with poor clinical outcome in oral cancer.

PubMed

Narayanan, Sathiya Pandi; Singh, Smriti; Gupta, Amit; Yadav, Sandhya; Singh, Shree Ram; Shukla, Sanjeev

2015-10-28

The histone demethylase KDM1A specifically demethylates lysine residues and its deregulation has been implicated in the initiation and progression of various cancers. However, KDM1A's molecular role and its pathological consequences, and prognostic significance in oral cancer remain less understood. In the present study, we sought to investigate the expression of KDM1A and its downstream role in oral cancer pathogenesis. By comparing mRNA expression profiles, we identified an elevated KDM1A expression in oral tumors when compared to normal oral tissues. In silico pathway prediction identified the association between KDM1A and E2F1 signaling in oral cancer. Pathway scanning, functional annotation analysis and In vitro assays showed the KDM1A's involvement in oral cancer cell proliferation and the cell cycle. Moreover, real time PCR and luciferase assays confirmed KDM1A's role in regulation of E2F1 signaling activity in oral cancer. Elevated KDM1A expression is associated with poor clinical outcome in oral cancer. Our data indicate that deregulated KDM1A expression is positively associated with proliferative phenotype of oral cancer and confers poor clinical outcome. These cumulative data suggest that KDM1A might be a potential diagnostic and therapeutic target for oral cancer. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Multivariate analysis of prognostic factors in synovial sarcoma.

PubMed

Koh, Kyoung Hwan; Cho, Eun Yoon; Kim, Dong Wook; Seo, Sung Wook

2009-11-01

Many studies have described the diversity of synovial sarcoma in terms of its biological characteristics and clinical features. Moreover, much effort has been expended on the identification of prognostic factors because of unpredictable behaviors of synovial sarcomas. However, with the exception of tumor size, published results have been inconsistent. We attempted to identify independent risk factors using survival analysis. Forty-one consecutive patients with synovial sarcoma were prospectively followed from January 1997 to March 2008. Overall and progression-free survival for age, sex, tumor size, tumor location, metastasis at presentation, histologic subtype, chemotherapy, radiation therapy, and resection margin were analyzed, and standard multivariate Cox proportional hazard regression analysis was used to evaluate potential prognostic factors. Tumor size (>5 cm), nonlimb-based tumors, metastasis at presentation, and a monophasic subtype were associated with poorer overall survival. Multivariate analysis showed metastasis at presentation and monophasic tumor subtype affected overall survival. For the progression-free survival, monophasic subtype was found to be only 1 prognostic factor. The study confirmed that histologic subtype is the single most important independent prognostic factors of synovial sarcoma regardless of tumor stage.

Prognostic Disclosures to Children: A Historical Perspective.

PubMed

Sisk, Bryan A; Bluebond-Langner, Myra; Wiener, Lori; Mack, Jennifer; Wolfe, Joanne

2016-09-01

Prognostic disclosure to children has perpetually challenged clinicians and parents. In this article, we review the historical literature on prognostic disclosure to children in the United States using cancer as an illness model. Before 1948, there was virtually no literature focused on prognostic disclosure to children. As articles began to be published in the 1950s and 1960s, many clinicians and researchers initially recommended a "protective" approach to disclosure, where children were shielded from the harms of bad news. We identified 4 main arguments in the literature at this time supporting this "protective" approach. By the late 1960s, however, a growing number of clinicians and researchers were recommending a more "open" approach, where children were included in discussions of diagnosis, which at the time was often synonymous with a terminal prognosis. Four different arguments in the literature were used at this time supporting this "open" approach. Then, by the late 1980s, the recommended approach to prognostic disclosure in pediatrics shifted largely from "never tell" to "always tell." In recent years, however, there has been a growing appreciation for the complexity of prognostic disclosure in pediatrics. Current understanding of pediatric disclosure does not lead to simple "black-and-white" recommendations for disclosure practices. As with most difficult questions, we are left to balance competing factors on a case-by-case basis. We highlight 4 categories of current considerations related to prognostic disclosure in pediatrics, and we offer several approaches to prognostic disclosure for clinicians who care for these young patients and their families. Copyright © 2016 by the American Academy of Pediatrics.

Refining prognosis in lung cancer: A report on the quality and relevance of clinical prognostic tools

PubMed Central

Mahar, Alyson L.; Compton, Carolyn; McShane, Lisa M.; Halabi, Susan; Asamura, Hisao; Rami-Porta, Ramon; Groome, Patti A.

2015-01-01

Introduction Accurate, individualized prognostication for lung cancer patients requires the integration of standard patient and pathologic factors, biologic, genetic, and other molecular characteristics of the tumor. Clinical prognostic tools aim to aggregate information on an individual patient to predict disease outcomes such as overall survival, but little is known about their clinical utility and accuracy in lung cancer. Methods A systematic search of the scientific literature for clinical prognostic tools in lung cancer published Jan 1, 1996-Jan 27, 2015 was performed. In addition, web-based resources were searched. A priori criteria determined by the Molecular Modellers Working Group of the American Joint Committee on Cancer were used to investigate the quality and usefulness of tools. Criteria included clinical presentation, model development approaches, validation strategies, and performance metrics. Results Thirty-two prognostic tools were identified. Patients with metastases were the most frequently considered population in non-small cell lung cancer. All tools for small cell lung cancer covered that entire patient population. Included prognostic factors varied considerably across tools. Internal validity was not formally evaluated for most tools and only eleven were evaluated for external validity. Two key considerations were highlighted for tool development: identification of an explicit purpose related to a relevant clinical population and clear decision-points, and prioritized inclusion of established prognostic factors over emerging factors. Conclusions Prognostic tools will contribute more meaningfully to the practice of personalized medicine if better study design and analysis approaches are used in their development and validation. PMID:26313682

Do the key prognostic factors for non-specific neck pain have moderation effects? - A study protocol.

PubMed

Balasundaram, Arun Prasad; Robinson, Hilde Stendal; Vøllestad, Nina Køpke

2018-05-01

Neck pain is one of the common musculoskeletal conditions prevalent in the general population in Norway. Patients with neck pain, seek treatment from different health professionals such as general practitioners, physiotherapists, chiropractors and alternative medicine practitioners. The interventions for neck pain are typically provided in a primary care or specialised healthcare setting depending on the general practitioners' referral patterns. Clinicians are interested to know the various prognostic factors that can explain the recovery from neck pain. In order to know this, studies have explored and reported on a range of prognostic factors that contribute to the outcomes in patients with neck pain. This information is currently available only for neck pain following whiplash injury that has a traumatic origin. There is limited information on the role of prognostic factors specifically for non-specific neck pain without a traumatic episode. Moreover, there is a lack of data on whether there are interactions (moderation effects) between the prognostic factors. Therefore, we propose a hypothesis to elucidate whether the same set of prognostic factors found in neck pain associated with whiplash injuries are also identified in patients with neck pain without trauma. Additionally, we hypothesize that the association between a prognostic factor and the outcome variable (s) would be dependent on the third variable, thereby confirming the moderation effects. Clinicians could make informed decisions in the clinical management of neck pain with the knowledge of prognostic factors that explain the outcomes. It could also be used for the development of new interventions or for modifying the existing ones. Copyright © 2018 Elsevier Ltd. All rights reserved.

lncRNA co-expression network model for the prognostic analysis of acute myeloid leukemia

PubMed Central

Pan, Jia-Qi; Zhang, Yan-Qing; Wang, Jing-Hua; Xu, Ping; Wang, Wei

2017-01-01

Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy with great variability of prognostic behaviors. Previous studies have reported that long non-coding RNAs (lncRNAs) play an important role in AML and may thus be used as potential prognostic biomarkers. However, thus use of lncRNAs as prognostic biomarkers in AML and their detailed mechanisms of action in this disease have not yet been well characterized. For this purpose, in the present study, the expression levels of lncRNAs and mRNAs were calculated using the RNA-seq V2 data for AML, following which a lncRNA-lncRNA co-expression network (LLCN) was constructed. This revealed a total of 8 AML prognosis-related lncRNA modules were identified, which displayed a significant correlation with patient survival (p≤0.05). Subsequently, a prognosis-related lncRNA module pathway network was constructed to interpret the functional mechanism of the prognostic modules in AML. The results indicated that these prognostic modules were involved in the AML pathway, chemokine signaling pathway and WNT signaling pathway, all of which play important roles in AML. Furthermore, the investigation of lncRNAs in these prognostic modules suggested that an lncRNA (ZNF571-AS1) may be involved in AML via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway by regulating KIT and STAT5. The results of the present study not only provide potential lncRNA modules as prognostic biomarkers, but also provide further insight into the molecular mechanisms of action of lncRNAs. PMID:28204819

A Blueprint to Advance Colorectal Cancer Immunotherapies.

PubMed

Le, Dung T; Hubbard-Lucey, Vanessa M; Morse, Michael A; Heery, Christopher R; Dwyer, Andrea; Marsilje, Thomas H; Brodsky, Arthur N; Chan, Emily; Deming, Dustin A; Diaz, Luis A; Fridman, Wolf H; Goldberg, Richard M; Hamilton, Stanley R; Housseau, Franck; Jaffee, Elizabeth M; Kang, S Peter; Krishnamurthi, Smitha S; Lieu, Christopher H; Messersmith, Wells; Sears, Cynthia L; Segal, Neil H; Yang, Arvin; Moss, Rebecca A; Cha, Edward; O'Donnell-Tormey, Jill; Roach, Nancy; Davis, Anjelica Q; McAbee, Keavy; Worrall, Sharyn; Benson, Al B

2017-11-01

Immunotherapy is rapidly becoming a standard of care for many cancers. However, colorectal cancer had been generally resistant to immunotherapy, despite features in common with sensitive tumors. Observations of substantial clinical activity for checkpoint blockade in colorectal cancers with defective mismatch repair (microsatellite instability-high tumors) have reignited interest in the search for immunotherapies that could be extended to the larger microsatellite stable (MSS) population. The Cancer Research Institute and Fight Colorectal Cancer convened a group of scientists, clinicians, advocates, and industry experts in colorectal cancer and immunotherapy to compile ongoing research efforts, identify gaps in translational and clinical research, and provide a blueprint to advance immunotherapy. We identified lack of a T-cell inflamed phenotype (due to inadequate T-cell infiltration, inadequate T-cell activation, or T-cell suppression) as a broad potential explanation for failure of checkpoint blockade in MSS. The specific cellular and molecular underpinnings for these various mechanisms are unclear. Whether biomarkers with prognostic value, such as the immunoscores and IFN signatures, would also predict benefit for immunotherapies in MSS colon cancer is unknown, but if so, these and other biomarkers for measuring the potential for an immune response in patients with colorectal cancer will need to be incorporated into clinical guidelines. We have proposed a framework for research to identify immunologic factors that may be modulated to improve immunotherapy for colorectal cancer patients, with the goal that the biomarkers and treatment strategies identified will become part of the routine management of colorectal cancer. Cancer Immunol Res; 5(11); 942-9. ©2017 AACR . ©2017 American Association for Cancer Research.

Cluster analysis of spontaneous preterm birth phenotypes identifies potential associations among preterm birth mechanisms

PubMed Central

Esplin, M Sean; Manuck, Tracy A.; Varner, Michael W.; Christensen, Bryce; Biggio, Joseph; Bukowski, Radek; Parry, Samuel; Zhang, Heping; Huang, Hao; Andrews, William; Saade, George; Sadovsky, Yoel; Reddy, Uma M.; Ilekis, John

2015-01-01

Objective We sought to employ an innovative tool based on common biological pathways to identify specific phenotypes among women with spontaneous preterm birth (SPTB), in order to enhance investigators' ability to identify to highlight common mechanisms and underlying genetic factors responsible for SPTB. Study Design A secondary analysis of a prospective case-control multicenter study of SPTB. All cases delivered a preterm singleton at SPTB ≤34.0 weeks gestation. Each woman was assessed for the presence of underlying SPTB etiologies. A hierarchical cluster analysis was used to identify groups of women with homogeneous phenotypic profiles. One of the phenotypic clusters was selected for candidate gene association analysis using VEGAS software. Results 1028 women with SPTB were assigned phenotypes. Hierarchical clustering of the phenotypes revealed five major clusters. Cluster 1 (N=445) was characterized by maternal stress, cluster 2 (N=294) by premature membrane rupture, cluster 3 (N=120) by familial factors, and cluster 4 (N=63) by maternal comorbidities. Cluster 5 (N=106) was multifactorial, characterized by infection (INF), decidual hemorrhage (DH) and placental dysfunction (PD). These three phenotypes were highly correlated by Chi-square analysis [PD and DH (p<2.2e-6); PD and INF (p=6.2e-10); INF and DH (p=0.0036)]. Gene-based testing identified the INS (insulin) gene as significantly associated with cluster 3 of SPTB. Conclusion We identified 5 major clusters of SPTB based on a phenotype tool and hierarchal clustering. There was significant correlation between several of the phenotypes. The INS gene was associated with familial factors underlying SPTB. PMID:26070700

The Glasgow Prognostic Score, an inflammation based prognostic score, predicts survival in patients with hepatocellular carcinoma

PubMed Central

2013-01-01

Background Elevated Glasgow Prognostic Score (GPS) has been related to poor prognosis in patients with hepatocellular carcinoma (HCC) undergoing surgical resection or receiving sorafenib. The aim of this study was to investigate the prognostic value of GPS in patients with various stages of the disease and with different liver functional status. Methods One hundred and fifty patients with newly diagnosed HCC were prospectively evaluated. Patients were divided according to their GPS scores. Univariate and multivariate analyses were performed to identify clinicopathological variables associated with overall survival; the identified variables were then compared with those of other validated staging systems. Results Elevated GPS were associated with increased asparate aminotransferase (P<0.0001), total bilirubin (P<0.0001), decreased albumin (P<0.0001), α-fetoprotein (P=0.008), larger tumor diameter (P=0.003), tumor number (P=0.041), vascular invasion (P=0.0002), extra hepatic metastasis (P=0.02), higher Child-Pugh scores (P<0.0001), and higher Cancer Liver Italian Program scores (P<0.0001). On multivariate analysis, the elevated GPS was independently associated with worse overall survival. Conclusions Our results demonstrate that the GPS can serve as an independent marker of poor prognosis in patients with HCC in various stages of disease and different liver functional status. PMID:23374755

Epidermal Growth Factor Receptor Tyrosine Kinase Defines Critical Prognostic Genes of Stage I Lung Adenocarcinoma

PubMed Central

Nagasaki, Masao; Shimamura, Teppei; Imoto, Seiya; Saito, Ayumu; Ueno, Kazuko; Hatanaka, Yousuke; Yoshida, Ryo; Higuchi, Tomoyuki; Nomura, Masaharu; Beer, David G.; Yokota, Jun; Miyano, Satoru; Gotoh, Noriko

2012-01-01

Purpose To identify stage I lung adenocarcinoma patients with a poor prognosis who will benefit from adjuvant therapy. Patients and Methods Whole gene expression profiles were obtained at 19 time points over a 48-hour time course from human primary lung epithelial cells that were stimulated with epidermal growth factor (EGF) in the presence or absence of a clinically used EGF receptor tyrosine kinase (RTK)-specific inhibitor, gefitinib. The data were subjected to a mathematical simulation using the State Space Model (SSM). “Gefitinib-sensitive” genes, the expressional dynamics of which were altered by addition of gefitinib, were identified. A risk scoring model was constructed to classify high- or low-risk patients based on expression signatures of 139 gefitinib-sensitive genes in lung cancer using a training data set of 253 lung adenocarcinomas of North American cohort. The predictive ability of the risk scoring model was examined in independent cohorts of surgical specimens of lung cancer. Results The risk scoring model enabled the identification of high-risk stage IA and IB cases in another North American cohort for overall survival (OS) with a hazard ratio (HR) of 7.16 (P = 0.029) and 3.26 (P = 0.0072), respectively. It also enabled the identification of high-risk stage I cases without bronchioalveolar carcinoma (BAC) histology in a Japanese cohort for OS and recurrence-free survival (RFS) with HRs of 8.79 (P = 0.001) and 3.72 (P = 0.0049), respectively. Conclusion The set of 139 gefitinib-sensitive genes includes many genes known to be involved in biological aspects of cancer phenotypes, but not known to be involved in EGF signaling. The present result strongly re-emphasizes that EGF signaling status in cancer cells underlies an aggressive phenotype of cancer cells, which is useful for the selection of early-stage lung adenocarcinoma patients with a poor prognosis. Trial Registration The Gene Expression Omnibus (GEO) GSE31210 PMID:23028479

Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia

PubMed Central

Geng, Huimin; Brennan, Sarah; Milne, Thomas A.; Chen, Wei-Yi; Li, Yushan; Hurtz, Christian; Kweon, Soo-Mi; Zickl, Lynette; Shojaee, Seyedmehdi; Neuberg, Donna; Huang, Chuanxin; Biswas, Debabrata; Xin, Yuan; Racevskis, Janis; Ketterling, Rhett P.; Luger, Selina M.; Lazarus, Hillard; Tallman, Martin S.; Rowe, Jacob M.; Litzow, Mark R.; Guzman, Monica L.; Allis, C. David; Roeder, Robert G.; Müschen, Markus; Paietta, Elisabeth; Elemento, Olivier; Melnick, Ari M.

2012-01-01

Genetic lesions such as BCR-ABL1, E2A-PBX1 and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point towards disease mechanisms and useful biomarkers and therapeutic targets. We therefore performed DNA methylation and gene expression profiling on a cohort of 215 adult B-ALL patients enrolled in a single phase III clinical trial (ECOG E2993) and normal control B-cells. In BCR-ABL1-positive B-ALL, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in ALL patients regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALL. In E2A-PBX1-positive B-ALL, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 ChIP sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6 targeted therapy as a new therapeutic strategy for MLLr B-ALL. PMID:23107779

Prognostic value of CpG island methylator phenotype among hepatocellular carcinoma patients: A systematic review and meta-analysis.

PubMed

Wang, Qian; Wang, Gang; Liu, Chaoxu; He, Xianli

2018-04-24

CpG island methylator phenotype (CIMP), characterized by multiple genes are concurrently methylated, has been reported to be associated with the prognosis of colorectal cancer. However, current studies have not explored the relationship between CIMP status with hepatocellular carcinoma (HCC) clinicopathological features. To assess these associations, we performed a comprehensive search of PubMed, EMBASE, and the Web of Science to identify all eligible studies. Publication bias was tested using Begg's and Egger's test. Seven studies that involved 568 HCC patients (379 CIMP+ and 189 CIMP-) were eligible for inclusion in our study. CIMP+ in HCC was significantly associated with distant metastasis (OR = 4.28, 95% CI = 2.57-7.10, P < 0.00001, heterogeneity = 0.888), TNM tumor stage IIII + IV (OR = 5.73, 95% CI = 3.70-8.88, P < 0.0001, heterogeneity = 0.449), cirrhosis (OR = 2.54, 95% CI = 1.33,4.83, P = 0.005, heterogeneity = 0.121) and a higher level of AFP (>300 ng/ml) than those with CIMP- (OR = 2.63, 95% CI = 1.79,3.89, P < 0.00001, heterogeneity = 0.432). Moreover, CIMP+ was associated with an unfavorable overall survival (OS) (HR = 3.02, 95% CI = 1.60-5.70, P < 0.001, heterogeneity = 0.251) and a disease-free survival (DFS) (HR = 2.80, 95% CI = 1.79-4.37, P < 0.001, heterogeneity = 0.603). CIMP is independently associated with significantly worse prognosis in HCC patients. Examination of CIMP status may be useful for identifying patients who are at higher risk for disease progression. Copyright © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

Pretreatment 18F-FDG PET Textural Features in Locally Advanced Non-Small Cell Lung Cancer: Secondary Analysis of ACRIN 6668/RTOG 0235.

PubMed

Ohri, Nitin; Duan, Fenghai; Snyder, Bradley S; Wei, Bo; Machtay, Mitchell; Alavi, Abass; Siegel, Barry A; Johnson, Douglas W; Bradley, Jeffrey D; DeNittis, Albert; Werner-Wasik, Maria; El Naqa, Issam

2016-06-01

In a secondary analysis of American College of Radiology Imaging Network (ACRIN) 6668/RTOG 0235, high pretreatment metabolic tumor volume (MTV) on (18)F-FDG PET was found to be a poor prognostic factor for patients treated with chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC). Here we utilize the same dataset to explore whether heterogeneity metrics based on PET textural features can provide additional prognostic information. Patients with locally advanced NSCLC underwent (18)F-FDG PET prior to treatment. A gradient-based segmentation tool was used to contour each patient's primary tumor. MTV, maximum SUV, and 43 textural features were extracted for each tumor. To address overfitting and high collinearity among PET features, the least absolute shrinkage and selection operator (LASSO) method was applied to identify features that were independent predictors of overall survival (OS) after adjusting for MTV. Recursive binary partitioning in a conditional inference framework was utilized to identify optimal thresholds. Kaplan-Meier curves and log-rank testing were used to compare outcomes among patient groups. Two hundred one patients met inclusion criteria. The LASSO procedure identified 1 textural feature (SumMean) as an independent predictor of OS. The optimal cutpoint for MTV was 93.3 cm(3), and the optimal SumMean cutpoint for tumors above 93.3 cm(3) was 0.018. This grouped patients into three categories: low tumor MTV (n = 155; median OS, 22.6 mo), high tumor MTV and high SumMean (n = 23; median OS, 20.0 mo), and high tumor MTV and low SumMean (n = 23; median OS, 6.2 mo; log-rank P < 0.001). We have described an appropriate methodology to evaluate the prognostic value of textural PET features in the context of established prognostic factors. We have also identified a promising feature that may have prognostic value in locally advanced NSCLC patients with large tumors who are treated with chemoradiotherapy. Validation studies are warranted. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Pretreatment 18F-FDG PET Textural Features in Locally Advanced Non–Small Cell Lung Cancer: Secondary Analysis of ACRIN 6668/RTOG 0235

PubMed Central

Ohri, Nitin; Duan, Fenghai; Snyder, Bradley S.; Wei, Bo; Machtay, Mitchell; Alavi, Abass; Siegel, Barry A.; Johnson, Douglas W.; Bradley, Jeffrey D.; DeNittis, Albert; Werner-Wasik, Maria; El Naqa, Issam

2016-01-01

In a secondary analysis of American College of Radiology Imaging Network (ACRIN) 6668/RTOG 0235, high pretreatment metabolic tumor volume (MTV) on 18F-FDG PET was found to be a poor prognostic factor for patients treated with chemoradiotherapy for locally advanced non–small cell lung cancer (NSCLC). Here we utilize the same dataset to explore whether heterogeneity metrics based on PET textural features can provide additional prognostic information. Methods Patients with locally advanced NSCLC underwent 18F-FDG PET prior to treatment. A gradient-based segmentation tool was used to contour each patient’s primary tumor. MTV, maximum SUV, and 43 textural features were extracted for each tumor. To address over-fitting and high collinearity among PET features, the least absolute shrinkage and selection operator (LASSO) method was applied to identify features that were independent predictors of overall survival (OS) after adjusting for MTV. Recursive binary partitioning in a conditional inference framework was utilized to identify optimal thresholds. Kaplan–Meier curves and log-rank testing were used to compare outcomes among patient groups. Results Two hundred one patients met inclusion criteria. The LASSO procedure identified 1 textural feature (SumMean) as an independent predictor of OS. The optimal cutpoint for MTV was 93.3 cm3, and the optimal Sum-Mean cutpoint for tumors above 93.3 cm3 was 0.018. This grouped patients into three categories: low tumor MTV (n = 155; median OS, 22.6 mo), high tumor MTV and high SumMean (n = 23; median OS, 20.0 mo), and high tumor MTV and low SumMean (n = 23; median OS, 6.2 mo; log-rank P < 0.001). Conclusion We have described an appropriate methodology to evaluate the prognostic value of textural PET features in the context of established prognostic factors. We have also identified a promising feature that may have prognostic value in locally advanced NSCLC patients with large tumors who are treated with chemoradiotherapy. Validation studies are warranted. PMID:26912429

Biological Marker Analysis as Part of the CIBERES-RTIC Cancer-SEPAR Strategic Project on Lung Cancer.

PubMed

Monsó, Eduard; Montuenga, Luis M; Sánchez de Cos, Julio; Villena, Cristina

2015-09-01

The aim of the Clinical and Molecular Staging of Stage I-IIp Lung Cancer Project is to identify molecular variables that improve the prognostic and predictive accuracy of TMN classification in stage I/IIp non-small cell lung cancer (NSCLC). Clinical data and lung tissue, tumor and blood samples will be collected from 3 patient cohorts created for this purpose. The prognostic protein signature will be validated from these samples, and micro-RNA, ALK, Ros1, Pdl-1, and TKT, TKTL1 y G6PD expression will be analyzed. Tissue inflammatory markers and stromal cell markers will also be analyzed. Methylation of p16, DAPK, RASSF1a, APC and CDH13 genes in the tissue samples will be determined, and inflammatory markers in peripheral blood will also be analyzed. Variables that improve the prognostic and predictive accuracy of TNM in NSCLC by molecular staging may be identified from this extensive analytical panel. Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.

Insulin-like growth factor II messenger RNA-binding protein-3 is an independent prognostic factor in uterine leiomyosarcoma.

PubMed

Yasutake, Nobuko; Ohishi, Yoshihiro; Taguchi, Kenichi; Hiraki, Yuka; Oya, Masafumi; Oshiro, Yumi; Mine, Mari; Iwasaki, Takeshi; Yamamoto, Hidetaka; Kohashi, Kenichi; Sonoda, Kenzo; Kato, Kiyoko; Oda, Yoshinao

2018-04-01

The aim of this study was to identify the prognostic factors of uterine leiomyosarcoma (ULMS). We reviewed 60 cases of surgically resected ULMSs and investigated conventional clinicopathological factors, together with the expression of insulin-like growth factor II messenger RNA-binding protein-3 (IMP3), hormone receptors and cell cycle regulatory markers by immunohistochemistry. Mediator complex subunit 12 (MED12) mutation analysis was also performed. Univariate analyses revealed that advanced stage (P < 0.0001), older age (P = 0.0244) and IMP3 expression (P = 0.0011) were significant predictors of a poor outcome. Multivariate analysis revealed advanced stage (P < 0.0001) and IMP3 (P = 0.0373) as independent predictors of a poor prognosis. Expressions of cell cycle markers and hormone receptors, and MED12 mutations (12% in ULMSs) were not identified as prognostic markers in this study. IMP3 expression in ULMS could be a marker of a poor prognosis. © 2017 John Wiley & Sons Ltd.

Neuropathic pain phenotyping by international consensus (NeuroPPIC) for genetic studies: a NeuPSIG systematic review, Delphi survey, and expert panel recommendations

PubMed Central

van Hecke, Oliver; Kamerman, Peter R.; Attal, Nadine; Baron, Ralf; Bjornsdottir, Gyda; Bennett, David L.H.; Bennett, Michael I.; Bouhassira, Didier; Diatchenko, Luda; Freeman, Roy; Freynhagen, Rainer; Haanpää, Maija; Jensen, Troels S.; Raja, Srinivasa N.; Rice, Andrew S.C.; Seltzer, Ze'ev; Thorgeirsson, Thorgeir E.; Yarnitsky, David; Smith, Blair H.

2015-01-01

Abstract For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic “entry level” set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of “possible” neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC “entry level” set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability. PMID:26469320

Prognostic significance of pretreatment neutrophil-to-lymphocyte ratio in melanoma patients: A meta-analysis.

PubMed

Zhan, Hui; Ma, Jian-Ying; Jian, Qi-Chao

2018-05-29

Recently, the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) has been widely evaluated in many cancers. Here we assessed the prognostic value of pretreatment NLR in melanoma. A range of online databases was systematically searched up to March,2018 for identify available studies which assessed the prognostic significance of NLR. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) were weighted by generic inverse-variance and pooled in random effects meta-analysis. Twelve studies with 4593 individuals were included. Patients with elevated NLR had a significantly shorter overall survival (OS) (HR: 1.56, 95% CI: 1.28-1.90, p < .001) and disease-free survival (DFS)/progression-free survival (PFS) (HR = 1.86; 95% CI = 1.24-2.80; P = .003). Subgroup analyses showed that the negative prognostic effect of elevated NLR on OS remained substantial in North American and Europen populations and patients with non-metastatic and metastatic stage. Additionally, elevated NLR was related to worse OS in patients with melanoma, regardless of the sample size and the cut-off value. Our findings suggest that elevated pretreatment NLR was associated with poor prognosis in melanoma patients, suggesting NLR might be a prognostic factor in patients with melanoma. Copyright © 2018 Elsevier B.V. All rights reserved.

Prognostic risk stratification derived from individual patient level data for men with advanced penile squamous cell carcinoma receiving first-line systemic therapy.

PubMed

Pond, Gregory R; Di Lorenzo, Giuseppe; Necchi, Andrea; Eigl, Bernhard J; Kolinsky, Michael P; Chacko, Raju T; Dorff, Tanya B; Harshman, Lauren C; Milowsky, Matthew I; Lee, Richard J; Galsky, Matthew D; Federico, Piera; Bolger, Graeme; DeShazo, Mollie; Mehta, Amitkumar; Goyal, Jatinder; Sonpavde, Guru

2014-05-01

Prognostic factors in men with penile squamous cell carcinoma (PSCC) receiving systemic therapy are unknown. A prognostic classification system in this disease may facilitate interpretation of outcomes and guide rational drug development. We performed a retrospective analysis to identify prognostic factors in men with PSCC receiving first-line systemic therapy for advanced disease. Individual patient level data were obtained from 13 institutions to study prognostic factors in the context of first-line systemic therapy for advanced PSCC. Cox proportional hazards regression analysis was conducted to examine the prognostic effect of these candidate factors on progression-free survival (PFS) and overall survival (OS): age, stage, hemoglobin, neutrophil count, lymphocyte count, albumin, site of metastasis (visceral or nonvisceral), smoking, circumcision, regimen, ECOG performance status (PS), lymphovascular invasion, precancerous lesion, and surgery following chemotherapy. The effect of different treatments was then evaluated adjusting for factors in the prognostic model. The study included 140 eligible men. Mean age across all men was 57.0 years. Among them, 8.6%, 21.4%, and 70.0% of patients had stage 2, 3, and 4 diseases, respectively; 40.7% had ECOG PS ≥ 1, 47.4% had visceral metastases, and 73.6% received cisplatin-based chemotherapy. The multivariate model of poor prognostic factors included visceral metastases (P<0.001) and ECOG PS ≥ 1 (P<0.001) for both PFS and OS. A risk stratification model constructed with 0, 1, and both poor prognostic factors was internally validated and demonstrated moderate discriminatory ability (c-statistic of 0.657 and 0.677 for OS and PFS, respectively). The median OS for the entire population was 9 months. Median OS was not reached, 8, and 7 months for those with 0, 1, and both risk factors, respectively. Cisplatin-based regimens were associated with better OS (P = 0.017) but not PFS (P = 0.37) compared with noncisplatin-based regimens after adjusting for the 2 prognostic factors. In men with advanced PSCC receiving first-line systemic therapy, visceral metastases and ECOG PS ≥ 1 were poor prognostic factors. A prognostic model including these factors exhibited moderate discriminatory ability for outcomes and warrants external validation. Patients receiving cisplatin-based regimens exhibited better outcomes compared with noncisplatin-based regimens after adjusting for prognostic factors. © 2013 Published by Elsevier Inc.

The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer

PubMed Central

Ling, Agnes; Lundberg, Ida V; Eklöf, Vincy; Wikberg, Maria L; Öberg, Åke; Palmqvist, Richard

2015-01-01

Abstract Giving strong prognostic information, T‐cell infiltration is on the verge of becoming an additional component in the routine clinical setting for classification of colorectal cancer (CRC). With a view to further improving the tools for prognostic evaluation, we have studied how Th1 lymphocyte infiltration correlates with prognosis not only by quantity, but also by subsite, within CRCs with different molecular characteristics (microsatellite instability, CpG island methylator phenotype status, and BRAF and KRAS mutational status). We evaluated the Th1 marker T‐bet by immunohistochemistry in 418 archival tumour tissue samples from patients who underwent surgical resection for CRC. We found that a high number of infiltrating Th1 lymphocytes is strongly associated with an improved prognosis in patients with CRC, irrespective of intratumoural subsite, and that both extent of infiltration and patient outcome differ according to molecular subgroup. In brief, microsatellite instability, CpG island methylator phenotype‐high and BRAF mutated tumours showed increased infiltration of Th1 lymphocytes, and the most pronounced prognostic effect of Th1 infiltration was found in these tumours. Interestingly, BRAF mutated tumours were found to be more highly infiltrated by Th1 lymphocytes than BRAF wild‐type tumours whereas the opposite was seen for KRAS mutated tumours. These differences could be explained at least partly by our finding that BRAF mutated, in contrast to KRAS mutated, CRC cell lines and tumour specimens expressed higher levels of the Th1‐attracting chemokine CXCL10, and reduced levels of CCL22 and TGFB1, stimulating Th2/Treg recruitment and polarisation. In conclusion, the strong prognostic importance of Th1 lymphocyte infiltration in CRC was found at all subsites evaluated, and it remained significant in multivariable analyses, indicating that T‐bet may be a valuable marker in the clinical setting. Our results also indicate that T‐bet is of value when analysed in molecular subgroups of CRC, allowing identification of patients with especially poor prognosis who are in need of extended treatment. PMID:27499912

Prognostic factors for return-to-work following surgery for carpal tunnel syndrome: a systematic review.

PubMed

Peters, Susan; Johnston, Venerina; Hines, Sonia; Ross, Mark; Coppieters, Michel

2016-09-01

Carpal tunnel syndrome (CTS) is a common problem, that can be effectively managed by surgery. Screening for prognostic factors is important to identify workers who are at a greater risk of a poor work outcome in order to implement tailored interventions to facilitate their return-to-work. To synthesize the best available evidence on the association of preoperative prognostic factors with work-related outcomes in people who have undergone carpal tunnel surgery. Participants included those who were employed at the time of surgery, underwent carpal tunnel surgery and planned to return-to-work. The primary outcome was return-to-work. Quantitative studies investigating at least one prognostic factor for a work-related outcome in studies of workers who had carpal tunnel surgery were considered. Eleven electronic databases were searched from their respective inception date up to July 2015. A total of 3893 publications were reviewed. The quality of the included studies was assessed by two reviewers using a modified version of an appraisal tool (Joanna Briggs Institute Meta-analysis of Statistical Assessment and Review Instrument [JBI-MAStARI]). The following criteria were evaluated: study population representativeness, clearly defined prognostic factors and outcomes, potential confounding variables and appropriate statistical analysis. Data extraction was performed using a modified version of the standardized extraction tool from JBI-MAStARI. Statistical pooling was not possible. Findings are presented in tables and narrative format. Eleven studies (13 publications) investigating 93 prognostic factors for delayed return-to-work or prolonged work disability outcomes and 27 prognostic factors for work role functioning in 4187 participants were identified.Prognostic factors associated with workers' increased likelihood of an earlier return-to-work in a moderate-to-high-quality study included worker expected or desired fewer days off work, occupation, lower pain anxiety and if CTS had not altered their work role.Prognostic factors for a poorer work-related outcome included older age, lower household income, greater upper extremity functional limitation, greater than two musculoskeletal pain sites, lower recovery expectations, worse mental health status, job accommodation availability, high job strain, high job demands with high job control, poor co-worker relationships, poor baseline work role functioning, less-supportive workplace policies, preoperative work absence due to CTS or work disability of any cause, workers' compensation status, attorney involvement, and post-diagnosis surgical wait time. For workers who have had carpal tunnel surgery, there are a number of factors which may be modified in order to improve return-to-work times.

Expression profiling of nuclear receptors in breast cancer identifies TLX as a mediator of growth and invasion in triple-negative breast cancer.

PubMed

Lin, Meng-Lay; Patel, Hetal; Remenyi, Judit; Banerji, Christopher R S; Lai, Chun-Fui; Periyasamy, Manikandan; Lombardo, Ylenia; Busonero, Claudia; Ottaviani, Silvia; Passey, Alun; Quinlan, Philip R; Purdie, Colin A; Jordan, Lee B; Thompson, Alastair M; Finn, Richard S; Rueda, Oscar M; Caldas, Carlos; Gil, Jesus; Coombes, R Charles; Fuller-Pace, Frances V; Teschendorff, Andrew E; Buluwela, Laki; Ali, Simak

2015-08-28

The Nuclear Receptor (NR) superfamily of transcription factors comprises 48 members, several of which have been implicated in breast cancer. Most important is estrogen receptor-α (ERα), which is a key therapeutic target. ERα action is facilitated by co-operativity with other NR and there is evidence that ERα function may be recapitulated by other NRs in ERα-negative breast cancer. In order to examine the inter-relationships between nuclear receptors, and to obtain evidence for previously unsuspected roles for any NRs, we undertook quantitative RT-PCR and bioinformatics analysis to examine their expression in breast cancer. While most NRs were expressed, bioinformatic analyses differentiated tumours into distinct prognostic groups that were validated by analyzing public microarray data sets. Although ERα and progesterone receptor were dominant in distinguishing prognostic groups, other NR strengthened these groups. Clustering analysis identified several family members with potential importance in breast cancer. Specifically, RORγ is identified as being co-expressed with ERα, whilst several NRs are preferentially expressed in ERα-negative disease, with TLX expression being prognostic in this subtype. Functional studies demonstrated the importance of TLX in regulating growth and invasion in ERα-negative breast cancer cells.

Pre-treatment plasma proteomic markers associated with survival in oesophageal cancer

PubMed Central

Kelly, P; Paulin, F; Lamont, D; Baker, L; Clearly, S; Exon, D; Thompson, A

2012-01-01

Background: The incidence of oesophageal adenocarcinoma is increasing worldwide but survival remains poor. Neoadjuvant chemotherapy can improve survival, but prognostic and predictive biomarkers are required. This study built upon preclinical approaches to identify prognostic plasma proteomic markers in oesophageal cancer. Methods: Plasma samples collected before and during the treatment of oesophageal cancer and non-cancer controls were analysed by surface-enhanced laser desorption/ionisation time-of-flight (SELDI-TOF) mass spectroscopy (MS). Protein peaks were identified by MS in tryptic digests of purified fractions. Associations between peak intensities obtained in the spectra and clinical endpoints (survival, disease-free survival) were tested by univariate (Fisher's exact test) and multivariate analysis (binary logistic regression). Results: Plasma protein peaks were identified that differed significantly (P<0.05, ANOVA) between the oesophageal cancer and control groups at baseline. Three peaks, confirmed as apolipoprotein A-I, serum amyloid A and transthyretin, in baseline (pre-treatment) samples were associated by univariate and multivariate analysis with disease-free survival and overall survival. Conclusion: Plasma proteins can be detected prior to treatment for oesophageal cancer that are associated with outcome and merit testing as prognostic and predictive markers of response to guide chemotherapy in oesophageal cancer. PMID:22294182

Pre-treatment plasma proteomic markers associated with survival in oesophageal cancer.

PubMed

Kelly, P; Paulin, F; Lamont, D; Baker, L; Clearly, S; Exon, D; Thompson, A

2012-02-28

The incidence of oesophageal adenocarcinoma is increasing worldwide but survival remains poor. Neoadjuvant chemotherapy can improve survival, but prognostic and predictive biomarkers are required. This study built upon preclinical approaches to identify prognostic plasma proteomic markers in oesophageal cancer. Plasma samples collected before and during the treatment of oesophageal cancer and non-cancer controls were analysed by surface-enhanced laser desorption/ionisation time-of-flight (SELDI-TOF) mass spectroscopy (MS). Protein peaks were identified by MS in tryptic digests of purified fractions. Associations between peak intensities obtained in the spectra and clinical endpoints (survival, disease-free survival) were tested by univariate (Fisher's exact test) and multivariate analysis (binary logistic regression). Plasma protein peaks were identified that differed significantly (P<0.05, ANOVA) between the oesophageal cancer and control groups at baseline. Three peaks, confirmed as apolipoprotein A-I, serum amyloid A and transthyretin, in baseline (pre-treatment) samples were associated by univariate and multivariate analysis with disease-free survival and overall survival. Plasma proteins can be detected prior to treatment for oesophageal cancer that are associated with outcome and merit testing as prognostic and predictive markers of response to guide chemotherapy in oesophageal cancer.

Predicting mortality in sick African children: the FEAST Paediatric Emergency Triage (PET) Score.

PubMed

George, Elizabeth C; Walker, A Sarah; Kiguli, Sarah; Olupot-Olupot, Peter; Opoka, Robert O; Engoru, Charles; Akech, Samuel O; Nyeko, Richard; Mtove, George; Reyburn, Hugh; Berkley, James A; Mpoya, Ayub; Levin, Michael; Crawley, Jane; Gibb, Diana M; Maitland, Kathryn; Babiker, Abdel G

2015-07-31

Mortality in paediatric emergency care units in Africa often occurs within the first 24 h of admission and remains high. Alongside effective triage systems, a practical clinical bedside risk score to identify those at greatest risk could contribute to reducing mortality. Data collected during the Fluid As Expansive Supportive Therapy (FEAST) trial, a multi-centre trial involving 3,170 severely ill African children, were analysed to identify clinical and laboratory prognostic factors for mortality. Multivariable Cox regression was used to build a model in this derivation dataset based on clinical parameters that could be quickly and easily assessed at the bedside. A score developed from the model coefficients was externally validated in two admissions datasets from Kilifi District Hospital, Kenya, and compared to published risk scores using Area Under the Receiver Operating Curve (AUROC) and Hosmer-Lemeshow tests. The Net Reclassification Index (NRI) was used to identify additional laboratory prognostic factors. A risk score using 8 clinical variables (temperature, heart rate, capillary refill time, conscious level, severe pallor, respiratory distress, lung crepitations, and weak pulse volume) was developed. The score ranged from 0-10 and had an AUROC of 0.82 (95 % CI, 0.77-0.87) in the FEAST trial derivation set. In the independent validation datasets, the score had an AUROC of 0.77 (95 % CI, 0.72-0.82) amongst admissions to a paediatric high dependency ward and 0.86 (95 % CI, 0.82-0.89) amongst general paediatric admissions. This discriminative ability was similar to, or better than other risk scores in the validation datasets. NRI identified lactate, blood urea nitrogen, and pH to be important prognostic laboratory variables that could add information to the clinical score. Eight clinical prognostic factors that could be rapidly assessed by healthcare staff for triage were combined to create the FEAST Paediatric Emergency Triage (PET) score and externally validated. The score discriminated those at highest risk of fatal outcome at the point of hospital admission and compared well to other published risk scores. Further laboratory tests were also identified as prognostic factors which could be added if resources were available or as indices of severity for comparison between centres in future research studies.

Gene expression profiling of canine osteosarcoma reveals genes associated with short and long survival times

PubMed Central

Selvarajah, Gayathri T; Kirpensteijn, Jolle; van Wolferen, Monique E; Rao, Nagesha AS; Fieten, Hille; Mol, Jan A

2009-01-01

Background Gene expression profiling of spontaneous tumors in the dog offers a unique translational opportunity to identify prognostic biomarkers and signaling pathways that are common to both canine and human. Osteosarcoma (OS) accounts for approximately 80% of all malignant bone tumors in the dog. Canine OS are highly comparable with their human counterpart with respect to histology, high metastatic rate and poor long-term survival. This study investigates the prognostic gene profile among thirty-two primary canine OS using canine specific cDNA microarrays representing 20,313 genes to identify genes and cellular signaling pathways associated with survival. This, the first report of its kind in dogs with OS, also demonstrates the advantages of cross-species comparison with human OS. Results The 32 tumors were classified into two prognostic groups based on survival time (ST). They were defined as short survivors (dogs with poor prognosis: surviving fewer than 6 months) and long survivors (dogs with better prognosis: surviving 6 months or longer). Fifty-one transcripts were found to be differentially expressed, with common upregulation of these genes in the short survivors. The overexpressed genes in short survivors are associated with possible roles in proliferation, drug resistance or metastasis. Several deregulated pathways identified in the present study, including Wnt signaling, Integrin signaling and Chemokine/cytokine signaling are comparable to the pathway analysis conducted on human OS gene profiles, emphasizing the value of the dog as an excellent model for humans. Conclusion A molecular-based method for discrimination of outcome for short and long survivors is useful for future prognostic stratification at initial diagnosis, where genes and pathways associated with cell cycle/proliferation, drug resistance and metastasis could be potential targets for diagnosis and therapy. The similarities between human and canine OS makes the dog a suitable pre-clinical model for future 'novel' therapeutic approaches where the current research has provided new insights on prognostic genes, molecular pathways and mechanisms involved in OS pathogenesis and disease progression. PMID:19735553

Management of hepatocellular carcinoma: Predictive value of immunohistochemical markers for postoperative survival

PubMed Central

Niu, Zhao-Shan; Niu, Xiao-Jun; Wang, Mei

2015-01-01

Hepatocellular carcinoma (HCC) accounts for over 90% of all primary liver cancers. With an ever increasing incidence trend year by year, it has become the third most common cause of death from cancer worldwide. Hepatic resection is generally considered to be one of the most effective therapies for HCC patients, however, there is a high risk of recurrence in postoperative HCC. In clinical practice, there exists an urgent need for valid prognostic markers to identify patients with prognosis, hence the importance of studies on prognostic markers in improving the prediction of HCC prognosis. This review focuses on the most promising immunohistochemical prognostic markers in predicting the postoperative survival of HCC patients. PMID:25624992

Diagnostic and prognostic epigenetic biomarkers in cancer.

PubMed

Costa-Pinheiro, Pedro; Montezuma, Diana; Henrique, Rui; Jerónimo, Carmen

2015-01-01

Growing cancer incidence and mortality worldwide demands development of accurate biomarkers to perfect detection, diagnosis, prognostication and monitoring. Urologic (prostate, bladder, kidney), lung, breast and colorectal cancers are the most common and despite major advances in their characterization, this has seldom translated into biomarkers amenable for clinical practice. Epigenetic alterations are innovative cancer biomarkers owing to stability, frequency, reversibility and accessibility in body fluids, entailing great potential of assay development to assist in patient management. Several studies identified putative epigenetic cancer biomarkers, some of which have been commercialized. However, large multicenter validation studies are required to foster translation to the clinics. Herein we review the most promising epigenetic detection, diagnostic, prognostic and predictive biomarkers for the most common cancers.

Biological significance of long non-coding RNA FTX expression in human colorectal cancer.

PubMed

Guo, Xiao-Bo; Hua, Zhu; Li, Chen; Peng, Li-Pan; Wang, Jing-Shen; Wang, Bo; Zhi, Qiao-Ming

2015-01-01

The purpose of this study was to determine the expression of long non-coding RNA (lncRNA) FTX and analyze its prognostic and biological significance in colorectal cancer (CRC). A quantitative reverse transcription PCR was performed to detect the expression of long non-coding RNA FTX in 35 pairs of colorectal cancer and corresponding noncancerous tissues. The expression of long non-coding RNA FTX was detected in 187 colorectal cancer tissues and its correlations with clinicopathological factors of patients were examined. Univariate and multivariate analyses were performed to analyze the prognostic significance of Long Non-coding RNA FTX expression. The effects of long non-coding RNA FTX expression on malignant phenotypes of colorectal cancer cells and its possible biological significances were further determined. Long non-coding RNA FTX was significantly upregulated in colorectal cancer tissues, and low long non-coding RNA FTX expression was significantly correlated with differentiation grade, lymph vascular invasion, and clinical stage. Patients with high long non-coding RNA FTX showed poorer overall survival than those with low long non-coding RNA FTX. Multivariate analyses indicated that status of long non-coding RNA FTX was an independent prognostic factor for patients. Functional analyses showed that upregulation of long non-coding RNA FTX significantly promoted growth, migration, invasion, and increased colony formation in colorectal cancer cells. Therefore, long non-coding RNA FTX may be a potential biomarker for predicting the survival of colorectal cancer patients and might be a molecular target for treatment of human colorectal cancer.

High expression of Y-box-binding protein 1 is associated with local recurrence and predicts poor outcome in patients with colorectal cancer

PubMed Central

Yan, Xuebing; Yan, Leilei; zhou, Jia; Liu, Sihong; Shan, Zezhi; Jiang, Chunyu; Tian, Yuan; Jin, Zhiming

2014-01-01

Colorectal cancer (CRC) is one of the most common and fatal malignancies worldwide. Novel prognostic biomarkers are urgently warranted to help improve the treatment of CRC. Y-box-binding protein 1 (YB-1) has been identified as a multifunctional oncoprotein in various malignancies. Our previous study has suggested that YB-1 may promote malignant progression of CRC cells in vitro. However, its clinical and prognostic significance in CRC patients remains unclear. In this study, the expression of YB-1 was examined in 32 fresh CRC tissues using quantitative real-time polymerase chain reaction (qRT-PCR) and in 170 paraffin-embedded CRC tissues using immunohistochemistry. The result of qRT-PCR demonstrated mRNA expression of YB-1 was increased in 26 of 32 (81.25%) of CRC patients. The statistical analysis based on immunohistochemical staining suggested that YB-1 expression was significantly correlated with tumor differentiation, tumor invasion, lymph node metastasis and Dukes’ classification (all P<0.05). Furthermore, we found that patients with high YB-1 expression had a poorer prognosis and were more likely to undergo local recurrence, compared to those with low YB-1 expression. We also identified that YB-1 expression, together with lymph node metastasis and Dukes’ classification were independent prognostic factors for CRC patients. In conclusion, our study for the first time demonstrated the clinical and prognostic significance of YB-1 in CRC and suggested that YB-1 is of great potential to be an attractive therapeutic target as well as prognostic biomarker for CRC patients. PMID:25674237

Low Tumor Infiltrating Mast Cell Density Confers Prognostic Benefit and Reflects Immunoactivation in Colorectal Cancer.

PubMed

Mao, Yihao; Feng, Qingyang; Zheng, Peng; Yang, Liangliang; Zhu, Dexiang; Chang, Wenju; Ji, Meiling; He, Guodong; Xu, Jianmin

2018-06-06

The role of mast cells (MCs) in colorectal cancer (CRC) progression was controversial. Thus, this study was designed to evaluate the prognostic value of MCs as well as their correlation with immune microenvironment. A retrospective cohort of CRC patients of stage I-IV was enrolled in this study. 854 consecutive patients were divided into training set (427 patients) and validation set (427 patients) randomly. The findings were further validated in a GEO cohort, GSE39582 (556 patients). The mast cell density (MCD) was measured by immunohistochemical staining of tryptase or by CIBERSORT algorithm. Low MCD predicted prolonged overall survival (OS) in training and validation set. Moreover, MCD was identified as an independent prognostic indicator in both sets. Better stratification for CRC prognosis can be achieved by building a MCD based nomogram. The prognostic role of MCD was further validated in GSE39582. In addition, MCD predicted improved survival in stage II and III CRC patients receiving adjuvant chemotherapy (ACT). Multiple immune pathways were enriched in low MCD group while cytokines/chemokines promoting anti-tumor immunity were highly expressed in such group. Furthermore, MCD was negatively correlated with CD8+ T cells infiltration. In conclusion, MCD was identified as an independent prognostic factor, as well as a potential biomarker for ACT benefit in stage II and III CRC. Better stratification of CRC prognosis could be achieved by building a MCD based nomogram. Moreover, immunoactivation in low MCD tumors may contributed to improved prognosis. This article is protected by copyright. All rights reserved. © 2018 UICC.

Predictive factors of tumor control and survival after radiosurgery for local failures of nasopharyngeal carcinoma.

PubMed

Chua, Daniel T T; Sham, Jonathan S T; Hung, Kwan-Ngai; Leung, Lucullus H T; Au, Gordon K H

2006-12-01

Stereotactic radiosurgery has been employed as a salvage treatment of local failures of nasopharyngeal carcinoma (NPC). To identify patients that would benefit from radiosurgery, we reviewed our data with emphasis on factors that predicted treatment outcome. A total of 48 patients with local failures of NPC were treated by stereotactic radiosurgery between March 1996 and February 2005. Radiosurgery was administered using a modified linear accelerator with single or multiple isocenters to deliver a median dose of 12.5 Gy to the target periphery. Median follow-up was 54 months. Five-year local failure-free probability after radiosurgery was 47.2% and 5-year overall survival rate was 46.9%. Neuroendocrine complications occurred in 27% of patients but there were no treatment-related deaths. Time interval from primary radiotherapy, retreatment T stage, prior local failures and tumor volume were significant predictive factors of local control and/or survival whereas age was of marginal significance in predicting survival. A radiosurgery prognostic scoring system was designed based on these predictive factors. Five-year local failure-free probabilities in patients with good, intermediate and poor prognostic scores were 100%, 42.5%, and 9.6%. The corresponding five-year overall survival rates were 100%, 51.1%, and 0%. Important factors that predicted tumor control and survival after radiosurgery were identified. Patients with good prognostic score should be treated by radiosurgery in view of the excellent results. Patients with intermediate prognostic score may also be treated by radiosurgery but those with poor prognostic score should receive other salvage treatments.

Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis

PubMed Central

Pichler, Martin; Stiegelbauer, Verena; Vychytilova-Faltejskova, Petra; Ivan, Cristina; Ling, Hui; Winter, Elke; Zhang, Xinna; Goblirsch, Matthew; Wulf-Goldenberg, Annika; Ohtsuka, Masahisa; Haybaeck, Johannes; Svoboda, Marek; Okugawa, Yoshinaga; Gerger, Armin; Hoefler, Gerald; Goel, Ajay; Slaby, Ondrej; Calin, George Adrian

2017-01-01

Purpose Characterization of colorectal cancer transcriptome by high-throughput techniques has enabled the discovery of several differentially expressed genes involving previously unreported miRNA abnormalities. Here, we followed a systematic approach on a global scale to identify miRNAs as clinical outcome predictors and further validated them in the clinical and experimental setting. Experimental Design Genome-wide miRNA sequencing data of 228 colorectal cancer patients from The Cancer Genome Atlas dataset were analyzed as a screening cohort to identify miRNAs significantly associated with survival according to stringent prespecified criteria. A panel of six miRNAs was further validated for their prognostic utility in a large independent validation cohort (n = 332). In situ hybridization and functional experiments in a panel of colorectal cancer cell lines and xenografts further clarified the role of clinical relevant miRNAs. Results Six miRNAs (miR-92b-3p, miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p, and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR-188-3p expression proves to be an independent prognostic factor [screening cohort: HR = 4.137; 95% confidence interval (CI), 1.568–10.917; P = 0.004; validation cohort: HR = 1.538; 95% CI, 1.107–2.137; P = 0.010, respectively]. Forced miR-188-3p expression increased migratory behavior of colorectal cancer cells in vitro and metastases formation in vivo (P < 0.05). The promigratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in colorectal cancer cell migration. Conclusions miR-188-3p is a novel independent prognostic factor in colorectal cancer patients, which can be partly explained by its effect on MLLT4 expression and migration of cancer cells. PMID:27601590

Unique protein expression signatures of survival time in kidney renal clear cell carcinoma through a pan-cancer screening.

PubMed

Han, Guangchun; Zhao, Wei; Song, Xiaofeng; Kwok-Shing Ng, Patrick; Karam, Jose A; Jonasch, Eric; Mills, Gordon B; Zhao, Zhongming; Ding, Zhiyong; Jia, Peilin

2017-10-03

In 2016, it is estimated that there will be 62,700 new cases of kidney cancer in the United States, and 14,240 patients will die from the disease. Because the incidence of kidney renal clear cell carcinoma (KIRC), the most common type of kidney cancer, is expected to continue to increase in the US, there is an urgent need to find effective diagnostic biomarkers for KIRC that could help earlier detection of and customized treatment strategies for the disease. Accordingly, in this study we systematically investigated KIRC's prognostic biomarkers for survival using the reverse phase protein array (RPPA) data and the high throughput sequencing data from The Cancer Genome Atlas (TCGA). With comprehensive data available in TCGA, we systematically screened protein expression based survival biomarkers in 10 major cancer types, among which KIRC presented many protein prognostic biomarkers of survival time. This is in agreement with a previous report that expression level changes (mRNAs, microRNA and protein) may have a better performance for prognosis of KIRC. In this study, we also identified 52 prognostic genes for KIRC, many of which are involved in cell-cycle and cancer signaling, as well as 15 tumor-stage-specific prognostic biomarkers. Notably, we found fewer prognostic biomarkers for early-stage than for late-stage KIRC. Four biomarkers (the RPPA protein IDs: FASN, ACC1, Cyclin_B1 and Rad51) were found to be prognostic for survival based on both protein and mRNA expression data. Through pan-cancer screening, we found that many protein biomarkers were prognostic for patients' survival in KIRC. Stage-specific survival biomarkers in KIRC were also identified. Our study indicated that these protein biomarkers might have potential clinical value in terms of predicting survival in KIRC patients and developing individualized treatment strategies. Importantly, we found many biomarkers in KIRC at both the mRNA expression level and the protein expression level. These biomarkers shared a significant overlap, indicating that they were technically replicable.

A novel protein-based prognostic signature improves risk stratification to guide clinical management in early lung adenocarcinoma patients.

PubMed

Martínez-Terroba, Elena; Behrens, Carmen; de Miguel, Fernando J; Agorreta, Jackeline; Monsó, Eduard; Millares, Laura; Sainz, Cristina; Mesa-Guzman, Miguel; Pérez-Gracia, Jose Luis; Lozano, María Dolores; Zulueta, Javier J; Pio, Ruben; Wistuba, Ignacio I; Montuenga, Luis M; Pajares, María J

2018-05-13

Each of the pathological stages (I-IIIa) in which surgically resected non-small cell lung cancer patients are classified conceals hidden biological heterogeneity, manifested in heterogeneous outcomes within each stage. Thus, the finding of robust and precise molecular classifiers to assess individual patient risk is an unmet medical need. Here we identified and validated the clinical utility of a new prognostic signature based on three proteins (BRCA1, QKI and SLC2A1) to stratify early lung adenocarcinoma patients according to their risk of recurrence or death. Patients were staged following the new International Association for the Study of Lung Cancer (IASLC) staging criteria (8 th edition, 2018). A test cohort (n=239) was used to assess the value of this new prognostic index (PI) based on the three proteins. The prognostic signature was developed by Cox regression following stringent statistical criteria (TRIPOD: Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis). The model resulted in a highly significant predictor of five-year outcome for disease-free survival (P<0.001) and overall survival (P<0.001). The prognostic ability of the model was externally validated in an independent multi-institutional cohort of patients (n=114, P=0.021). We also demonstrated that this molecular classifier adds relevant information to the gold standard TNM-based pathological staging with a highly significant improvement of likelihood ratio. We subsequently developed a combined prognostic index (CPI) including both the molecular and the pathological data which improved the risk stratification in both cohorts (P≤0.001). Moreover, the signature may help to select stage I-IIA patients who might benefit from adjuvant chemotherapy. In summary, this protein-based signature accurately identifies those patients with high risk of recurrence and death, and adds further prognostic information to the TNM-based clinical staging, even applying the new IASLC 8 th edition staging criteria. More importantly, it may be a valuable tool for selecting patients for adjuvant therapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Geographic atrophy phenotype identification by cluster analysis.

PubMed

Monés, Jordi; Biarnés, Marc

2018-03-01

To identify ocular phenotypes in patients with geographic atrophy secondary to age-related macular degeneration (GA) using a data-driven cluster analysis. This was a retrospective analysis of data from a prospective, natural history study of patients with GA who were followed for ≥6 months. Cluster analysis was used to identify subgroups within the population based on the presence of several phenotypic features: soft drusen, reticular pseudodrusen (RPD), primary foveal atrophy, increased fundus autofluorescence (FAF), greyish FAF appearance and subfoveal choroidal thickness (SFCT). A comparison of features between the subgroups was conducted, and a qualitative description of the new phenotypes was proposed. The atrophy growth rate between phenotypes was then compared. Data were analysed from 77 eyes of 77 patients with GA. Cluster analysis identified three groups: phenotype 1 was characterised by high soft drusen load, foveal atrophy and slow growth; phenotype 3 showed high RPD load, extrafoveal and greyish FAF appearance and thin SFCT; the characteristics of phenotype 2 were midway between phenotypes 1 and 3. Phenotypes differed in all measured features (p≤0.013), with decreases in the presence of soft drusen, foveal atrophy and SFCT seen from phenotypes 1 to 3 and corresponding increases in high RPD load, high FAF and greyish FAF appearance. Atrophy growth rate differed between phenotypes 1, 2 and 3 (0.63, 1.91 and 1.73 mm 2 /year, respectively, p=0.0005). Cluster analysis identified three distinct phenotypes in GA. One of them showed a particularly slow growth pattern. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Machine-learning phenotypic classification of bicuspid aortopathy.

PubMed

Wojnarski, Charles M; Roselli, Eric E; Idrees, Jay J; Zhu, Yuanjia; Carnes, Theresa A; Lowry, Ashley M; Collier, Patrick H; Griffin, Brian; Ehrlinger, John; Blackstone, Eugene H; Svensson, Lars G; Lytle, Bruce W

2018-02-01

Bicuspid aortic valves (BAV) are associated with incompletely characterized aortopathy. Our objectives were to identify distinct patterns of aortopathy using machine-learning methods and characterize their association with valve morphology and patient characteristics. We analyzed preoperative 3-dimensional computed tomography reconstructions for 656 patients with BAV undergoing ascending aorta surgery between January 2002 and January 2014. Unsupervised partitioning around medoids was used to cluster aortic dimensions. Group differences were identified using polytomous random forest analysis. Three distinct aneurysm phenotypes were identified: root (n = 83; 13%), with predominant dilatation at sinuses of Valsalva; ascending (n = 364; 55%), with supracoronary enlargement rarely extending past the brachiocephalic artery; and arch (n = 209; 32%), with aortic arch dilatation. The arch phenotype had the greatest association with right-noncoronary cusp fusion: 29%, versus 13% for ascending and 15% for root phenotypes (P < .0001). Severe valve regurgitation was most prevalent in root phenotype (57%), followed by ascending (34%) and arch phenotypes (25%; P < .0001). Aortic stenosis was most prevalent in arch phenotype (62%), followed by ascending (50%) and root phenotypes (28%; P < .0001). Patient age increased as the extent of aneurysm became more distal (root, 49 years; ascending, 53 years; arch, 57 years; P < .0001), and root phenotype was associated with greater male predominance compared with ascending and arch phenotypes (94%, 76%, and 70%, respectively; P < .0001). Phenotypes were visually recognizable with 94% accuracy. Three distinct phenotypes of bicuspid valve-associated aortopathy were identified using machine-learning methodology. Patient characteristics and valvular dysfunction vary by phenotype, suggesting that the location of aortic pathology may be related to the underlying pathophysiology of this disease. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

The 2017 WHO update on mature T- and natural killer (NK) cell neoplasms.

PubMed

Matutes, E

2018-05-01

Over the last decade, there has been a significant body of information regarding the biology of the lymphoid neoplasms. This clearly supports the need for updating the 2008 WHO (World Health Organization) classification of haematopoietic and lymphoid tumours. The 2017 WHO classification is not a new edition but an update and revision of the 4th edition. New provisional entities but not new definitive entities are included, and novel molecular data in most of the entities and changes in the nomenclature in few of them have been incorporated. In the context of the mature T- and NK-cell neoplasms, the most relevant updates concern to: 1-dysregulation of the JAK/STAT pathway due to gene mutations which are common to various aggressive and indolent neoplasms; 2-incorporation of new molecular players that are relevant to the pathogenesis of these neoplasms and/or have prognostic implications; 3-inclusion of new provisional entities within the subgroups of anaplastic, primarily intestinal and cutaneous lymphomas such as breast implant-associated anaplastic large cell lymphoma, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract and primary cutaneous acral CD8 + T-cell lymphoma; 4-identification of poor prognostic subtypes of peripheral T-cell lymphomas not otherwise specified (PTCL, NOS) characterized by overexpression of certain genes and of a subgroup PTCL, NOS with a T follicular phenotype that now is included together with angioimmunoblastic T-cell lymphoma under the umbrella of lymphomas with a T follicular helper phenotype; and 5-refinement on the designation and definition of already established entities. A review of the major changes will be outlined. © 2018 John Wiley & Sons Ltd.

Evaluation of CpG Island Methylator Phenotype as a Biomarker in Colorectal Cancer Treated With Adjuvant Oxaliplatin.

PubMed

Cohen, Stacey A; Wu, Chen; Yu, Ming; Gourgioti, Georgia; Wirtz, Ralph; Raptou, Georgia; Gkakou, Chryssa; Kotoula, Vassiliki; Pentheroudakis, George; Papaxoinis, George; Karavasilis, Vasilios; Pectasides, Dimitrios; Kalogeras, Konstantine T; Fountzilas, George; Grady, William M

2016-06-01

The CpG island methylator phenotype (CIMP) is a promising biomarker for irinotecan/5-fluorouracil/leucovorin chemotherapy for stage III colon cancer. In the present study, we evaluated whether CIMP is a prognostic biomarker for standard-of-care oxaliplatin-based adjuvant therapy. The HE6C/05 trial randomized 441 patients with stage II-III colorectal adenocarcinoma to adjuvant XELOX (capecitabine, oxaliplatin) or modified FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin). The primary and secondary objectives were disease-free and overall survival, respectively. CIMP status was determined using the DNA methylation status of CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Cox models were used to assess the association of CIMP with survival. Of the 293 available tumors, 28 (9.6%) were CIMP(+). On univariate Cox regression analysis, no significant differences in survival were observed between individuals with CIMP(+) versus CIMP(-) tumors. CIMP(+) tumors were more likely to be right-sided and BRAF mutant (χ(2), P < .001). In the multivariate model, TNM stage II (vs. stage III) was associated with a reduced risk of relapse (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.11-0.55; Wald's P < .001), and a colon primary located on the left side and earlier TNM stage were associated with a reduced risk of death (HR, 0.48; 95% CI, 0.28-0.81; P = .006; and HR, 0.22; 95% CI, 0.10-0.49; P < .001, respectively). In the present exploratory analysis, CIMP did not appear to be a prognostic biomarker in oxaliplatin-treated patients with resected colorectal cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

Association between the CpG island methylator phenotype and its prognostic significance in primary pulmonary adenocarcinoma.

PubMed

Koh, Young Wha; Chun, Sung-Min; Park, Young-Soo; Song, Joon Seon; Lee, Geon Kook; Khang, Shin Kwang; Jang, Se Jin

2016-08-01

Aberrant methylation of promoter CpG islands is one of the most important inactivation mechanisms for tumor suppressor and tumor-related genes. Previous studies using genome-wide DNA methylation microarray analysis have suggested the existence of a CpG island methylator phenotype (CIMP) in lung adenocarcinomas. Although the biological behavior of these tumors varies according to tumor stage, no large-scale study has examined the CIMP in lung adenocarcinoma patients according to tumor stage. Furthermore, there have been no reported results regarding the clinical significance of each of the six CIMP markers. To examine the CIMP in patients with pulmonary adenocarcinoma after a surgical resection, we performed methylation analysis of six genes (CCNA1, ACAN, GFRA1, EDARADD, MGC45800, and p16 (INK4A)) in 230 pulmonary adenocarcinoma cases using the SEQUENOM MassARRAY platform. Fifty-four patients (28 %, 54/191) were in the CIMP-high (CIMP-H) group associated with high nodal stage (P = 0.007), the presence of micropapillary or solid histology (P = 0.003), and the absence of an epidermal growth factor receptor (EGFR) mutation (P = 0.002). By multivariate analysis, CIMP was an independent prognostic marker for overall survival (OS) and disease-specific survival (P = 0.03 and P = 0.43, respectively). In the stage I subgroups alone, CIMP-H patients had lower OS rates than the CIMP-low (CIMP-L) group (P = 0.041). Of the six CIMP markers, ACAN alone was significantly associated with patient survival. CIMP predicted the risk of progression independently of clinicopathological variables and enables the stratification of pulmonary adenocarcinoma patients, particularly among stage I cases.

The Distribution of Intratumoral Macrophages Correlates with Molecular Phenotypes and Impacts Prognosis in Colorectal Carcinoma.

PubMed

Kim, Younghoon; Wen, Xianyu; Bae, Jeong Mo; Kim, Jung Ho; Cho, Nam-Yun; Kang, Gyeong Hoon

2018-06-15

The role of tumor-associated macrophages (TAMs) in colorectal cancer (CRC) remains elusive. In this study, we aimed to examine the correlation between TAMs, clinicopathological features, tumor-infiltrating lymphocytes (TILs), and prognosis in CRC via image analysis. Immunohistochemical staining for CD68 and CD163 was performed with pan-macrophage and M2-macrophage markers, respectively. Each marker was separately analyzed for intraepithelial and stromal area densities. All four macrophage densities showed a significant correlation with one another (p = 0.001). Intraepithelial CD68+ macrophage densities showed a correlation with pTNM stage (p = 0.008), microsatellite instability (p < 0.001), CpG island methylator phenotype (p < 0.001), and TIL densities (p < 0.001). Intraepithelial CD163+ macrophage densities were associated with perineural invasion, MSI, CIMP, and TIL densities (p < 0.001). Stromal CD68+ and CD163+ macrophage densities had a significant relationship with Intraepithelial and stromal CD3+ (p = 0.001 and p < 0.001, respectively) and CD8+ (p < 0.001) T cells. High intraepithelial CD68+ macrophage density was associated with worse overall survival (HR = 1.386, 95% CI = 1.043-1.843, p = 0.025) and progression-free survival (HR = 1.522, 95% CI = 1.146-2.020, p = 0.004). Intraepithelial CD68+ macrophage density was also an independent prognostic factor of the progression-free survival (HR = 1.447, 95% CI = 1.076-1.947, p = 0.015) of CRC patients regardless of pTNM stage, lymphatic, venous, and perineural invasions, and TIL densities. Our results indicate that the density of intratumoral macrophages are useful prognostic indicator for further stratifying T cell populations in CRC. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors

PubMed Central

Biegstraaten, Marieke; Hughes, Derralynn A.; Mehta, Atul; Elliott, Perry M.; Oder, Daniel; Watkinson, Oliver T.; Vaz, Frédéric M.; van Kuilenburg, André B. P.; Wanner, Christoph; Hollak, Carla E. M.

2017-01-01

Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence. As expected, age, sex and phenotype were important predictors of event rate. Clinical events before enzyme replacement therapy, cardiac mass and eGFR at baseline predicted an increased event rate. eGFR was the most important predictor: hazard ratios increased from 2 at eGFR <90 ml/min/1.73m2 to 4 at eGFR <30, compared to patients with an eGFR >90. In addition, men with classical disease and a baseline eGFR <60 ml/min/1.73m2 had a faster yearly decline (-2.0 ml/min/1.73m2) than those with a baseline eGFR of >60. Proteinuria was a further independent risk factor for decline in eGFR. Increased cardiac mass at baseline was associated with the most robust decrease in cardiac mass during treatment, while presence of cardiac fibrosis predicted a stronger increase in cardiac mass (3.36 gram/m2/year). Of other cardiovascular risk factors, hypertension significantly predicted the risk for clinical events. In conclusion, besides increasing age, male sex and classical phenotype, faster disease progression while on enzyme replacement therapy is predicted by renal function, proteinuria and to a lesser extent cardiac fibrosis and hypertension. PMID:28763515

Fundus autofluorescence imaging in dry AMD: 2014 Jules Gonin lecture of the Retina Research Foundation.

PubMed

Holz, Frank G; Steinberg, Julia S; Göbel, Arno; Fleckenstein, Monika; Schmitz-Valckenberg, Steffen

2015-01-01

Fundus autofluorescence (FAF) imaging allows for topographic mapping of intrisnic fluorophores in the retinal pigment epithelial cell monolayer, as well as mapping of other fluorophores that may occur with disease in the outer retina and the sub-neurosensory space. FAF imaging provides information not obtainable with other imaging modalities. Near-infrared fundus autofluorescence images can also be obtained in vivo, and may be largely melanin-derived. FAF imaging has been shown to be useful in a wide spectrum of macular and retinal diseases. The scope of applications now includes identification of diseased RPE in macular/retinal diseases, elucidating pathophysiological mechanisms, identification of early disease stages, refined phenotyping, identification of prognostic markers for disease progression, monitoring disease progression in the context of both natural history and interventional therapeutic studies, and objective assessment of luteal pigment distribution and density as well as RPE melanin distribution. Here, we review the use of FAF imaging in various phenotypic manifestations of dry AMD.

Comparative study of the immunohistochemical phenotype in breast cancer and its lymph node metastatic location.

PubMed

De la Haba-Rodríguez, Juan R; Ruiz Borrego, Manuel; Gómez España, Auxiliadora; Villar Pastor, Carlos; Japón, Miguel A; Travado, Paulino; Moreno Nogueira, José Andrés; López Rubio, Fernando; Aranda Aguilar, Enrique

2004-01-01

At present, an important part of prognostic information, together with particular treatment strategies in breast cancer, take into account the immunohistochemical phenotype of the primary tumor location. However, the changing heterogeneity intrinsic to neoplastic cells in general leads us to consider the possibility that the expression of these proteins is modified during tumoral development and dissemination. With this hypothesis as a starting point, 60 patients with breast cancer were studied with immunohistochemistry, the expression of estrogen and progestagenic receptors, proliferation through the Ki-67 expression, and the overexpression of HER-2 and p53 in both the primary location and the lymph node metastases. If we consider significant change to be loss (from positive to negative) or gain (negative to positive) of expression in some of the studied determinations, we find that this is produced in 60% of the tumors studied. These results demonstrate the modification of immunohistochemical expression of the proteins studied between the primary tumor location and the lymph node metastases.

Diagnostic/prognostic molecular cytogenetic follow-up applied in satellited marker cases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Papenhausen, P.R.; Anderson, S.

1994-09-01

Special caution needs to be exercised in offering a good prognosis in Prader-Willi probe negative 15-derived marker cases, since it is clear that phenotypic effects can still be associated with the apparent presence of proximal sequences. We have had two postnatal cases in this category, one which was inherited from an unaffected paternal (non-mosaic) carrier, possibly demonstrating imprinting effects. Familial studies are continuing in this case. Although the D22/S9 locus appears diagnostic of cateye syndrome (CES), the dual specificity of the 14/22 centromeric probe leaves the possibility of a poor prognosis 14 derivation when the CES probe is negative. Therefore,more » it is imperative that proximal long arm 13, 14, 21 and more proximal 15 FISH probes be implemented so that a phenotypically correlated database may indicate the proper FISH probes necessary for accurate prognosis. Bisatellited markers is which a bipartite centromeric probe signal was found were considered to be higher risk than those with the single signal in counseling.« less

Axenfeld-Rieger syndrome: further clinical and array delineation of four unrelated patients with a 4q25 microdeletion.

PubMed

Titheradge, Hannah; Togneri, Fiona; McMullan, Dominic; Brueton, Louise; Lim, Derek; Williams, Denise

2014-07-01

Axenfeld-Rieger syndrome (ARS) is an autosomal dominant disorder with variable expressivity. It is characterized by dysgenesis of the anterior segment of the eye together with dental, cardiac, and umbilical anomalies. There is a high incidence of secondary high tension glaucoma. It is a genetically heterogeneous condition due to deletion or mutations of FOXC1 (6p25) or PITX2 (4q25). We report on four unrelated patients with overlapping microdeletions encompassing PITX2 at 4q25. We compare the genotypes and phenotypes of these newly described ARS patients and discuss the involvement of contiguous genes. Patients 1, 2, and 3 had mild learning difficulties, not typically seen in patients with ARS. We implicate the adjacent neuronally expressed genes; NEUROG2, UGT8, NDST3, and PRSS12 as potentially causal. Our findings support the use of microarray analysis in ARS patients for full prognostic information in infants presenting with ARS-like phenotypes. © 2014 Wiley Periodicals, Inc.

Adjusted Analyses in Studies Addressing Therapy and Harm: Users' Guides to the Medical Literature.

PubMed

Agoritsas, Thomas; Merglen, Arnaud; Shah, Nilay D; O'Donnell, Martin; Guyatt, Gordon H

2017-02-21

Observational studies almost always have bias because prognostic factors are unequally distributed between patients exposed or not exposed to an intervention. The standard approach to dealing with this problem is adjusted or stratified analysis. Its principle is to use measurement of risk factors to create prognostically homogeneous groups and to combine effect estimates across groups.The purpose of this Users' Guide is to introduce readers to fundamental concepts underlying adjustment as a way of dealing with prognostic imbalance and to the basic principles and relative trustworthiness of various adjustment strategies.One alternative to the standard approach is propensity analysis, in which groups are matched according to the likelihood of membership in exposed or unexposed groups. Propensity methods can deal with multiple prognostic factors, even if there are relatively few patients having outcome events. However, propensity methods do not address other limitations of traditional adjustment: investigators may not have measured all relevant prognostic factors (or not accurately), and unknown factors may bias the results.A second approach, instrumental variable analysis, relies on identifying a variable associated with the likelihood of receiving the intervention but not associated with any prognostic factor or with the outcome (other than through the intervention); this could mimic randomization. However, as with assumptions of other adjustment approaches, it is never certain if an instrumental variable analysis eliminates bias.Although all these approaches can reduce the risk of bias in observational studies, none replace the balance of both known and unknown prognostic factors offered by randomization.

Prognostic value of purinergic P2X7 receptor expression in patients with hepatocellular carcinoma after curative resection.

PubMed

Liu, Haiou; Liu, Weisi; Liu, Zheng; Liu, Yidong; Zhang, Weijuan; Xu, Le; Xu, Jiejie

2015-07-01

The family of type 2 purinergic (P2) receptors, especially P2X7, is responsible for the direct tumor-killing functions of extracellular adenosine triphosphate (ATP), but the precise role of P2X7 in the progression of hepatocellular carcinoma (HCC) remains elusive. This study aims to evaluate prognostic value of P2X7 expression in HCC patients after surgical resection. Expression of P2X7 was assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissues from 273 patients with HCC who had undergone hepatectomy between 2006 and 2007. Prognostic value of P2X7 expression and clinical outcomes were evaluated. Peritumoral P2X7 expression was significantly higher than intratumoral P2X7 expression. No significant prognostic difference was observed for overall survival for intratumoral P2X7 density, whereas peritumoral P2X7 density indicates unfavorable overall survival in training set and BCLC stage 0-A subset. Besides, peritumoral P2X7 density, which correlated with tumor size, venous invasion, and BCLC stage, was identified as an independent poor prognosticator for overall survival and recurrence-free survival. The association was further validated in validation set. Peritumoral P2X7 is a potential unfavorable prognosticator for overall survival and recurrence free survival in HCC patients after surgical resection. Further external validation and functional analysis should be pursued to evaluate its potential prognostic value and therapeutic significance for HCC patients.

Primary Tumor Thickness is a Prognostic Factor in Stage IV Melanoma: A Retrospective Study of Primary Tumor Characteristics.

PubMed

Luen, Stephen; Wong, Siew Wei; Mar, Victoria; Kelly, John W; McLean, Catriona; McArthur, Grant A; Haydon, Andrew

2018-01-01

Stage IV melanoma exhibits a diverse range of tumor biology from indolent to aggressive disease. Many important prognostic factors have already been identified. Despite this, the behavior of metastatic melanoma remains difficult to predict. We sought to determine if any primary tumor characteristics affect survival following the diagnosis of stage IV melanoma. All patients diagnosed with stage IV melanoma between January 2003 and December 2012 were identified from the Victorian Melanoma Service database. Retrospective chart review was performed to collect data on primary tumor characteristics (thickness, ulceration, mitotic rate, melanoma subtype, or occult primary). Known and suspected prognostic factors were additionally collected (time to diagnosis of stage IV disease, age, sex, stage, receipt of chemotherapy, and era of recurrence). The effect of primary tumor characteristics on overall survival from the date of diagnosis of stage IV disease was assessed. A total of 227 patients with a median follow-up of 5 years from diagnosis of stage IV disease were identified. Median overall survival of the cohort was 250 days.Of the primary tumor characteristics assessed, only tumor thickness affected survival from diagnosis of stage IV disease, hazard ratio=1.09 (1.02 to 1.16), P=0.008. This remained significant in multivariate analysis, P=0.007. Other primary tumor characteristics did not significantly influence survival. Primary tumor thickness is a significant prognostic factor in stage IV melanoma. Our data suggest that the biology of the primary melanoma may persist to influence the behavior of metastatic disease.

Development and Validation of a Novel Platform-Independent Metastasis Signature in Human Breast Cancer

PubMed Central

Speers, Corey; Liu, Meilan; Wilder-Romans, Kari; Lawrence, Theodore S.; Pierce, Lori J.; Feng, Felix Y.

2015-01-01

Purpose The molecular drivers of metastasis in breast cancer are not well understood. Therefore, we sought to identify the biological processes underlying distant progression and define a prognostic signature for metastatic potential in breast cancer. Experimental design In vivo screening for metastases was performed using Chick Chorioallantoic Membrane assays in 21 preclinical breast cancer models. Expressed genes associated with metastatic potential were identified using high-throughput analysis. Correlations with biological function were determined using the Database for Annotation, Visualization and Integrated Discovery. Results We identified a broad range of metastatic potential that was independent of intrinsic breast cancer subtypes. 146 genes were significantly associated with metastasis progression and were linked to cancer-related biological functions, including cell migration/adhesion, Jak-STAT, TGF-beta, and Wnt signaling. These genes were used to develop a platform-independent gene expression signature (M-Sig), which was trained and subsequently validated on 5 independent cohorts totaling nearly 1800 breast cancer patients with all p-values < 0.005 and hazard ratios ranging from approximately 2.5 to 3. On multivariate analysis accounting for standard clinicopathologic prognostic variables, M-Sig remained the strongest prognostic factor for metastatic progression, with p-values < 0.001 and hazard ratios > 2 in three different cohorts. Conclusion M-Sig is strongly prognostic for metastatic progression, and may provide clinical utility in combination with treatment prediction tools to better guide patient care. In addition, the platform-independent nature of the signature makes it an excellent research tool as it can be directly applied onto existing, and future, datasets. PMID:25974184

High Numbers of Stromal Cancer-Associated Fibroblasts Are Associated With a Shorter Survival Time in Cats With Oral Squamous Cell Carcinoma.

PubMed

Klobukowska, H J; Munday, J S

2016-11-01

Cancer-associated fibroblasts (CAFs) are fibroblastic cells that express α-smooth muscle actin and have been identified in the stroma of numerous epithelial tumors. The presence of CAFs within the tumor stroma has been associated with a poorer prognosis in some human cancers, including oral squamous cell carcinomas (SCCs). Cats frequently develop oral SCCs, and although these are generally highly aggressive neoplasms, there is currently a lack of prognostic markers for these tumors. The authors investigated the prognostic value of the presence of CAFs within the stroma of oral SCC biopsy specimens from 47 cats. In addition, several epidemiologic, clinical, and histologic variables were also assessed for prognostic significance. A CAF-positive stroma was identified in 35 of 47 SCCs (74.5%), and the median survival time (ST) of cats with CAF-positive SCCs (35 days) was significantly shorter than that of cats with CAF-negative SCCs (48.5 days) (P = .031). ST was also associated with the location of the primary tumor (P = .0018): the median ST for oropharyngeal SCCs (179 days) was significantly longer than for maxillary (43.5 days; P = .047), mandibular (42 days; P = .022), and sublingual SCCs (22.5 days; P = .0005). The median ST of sublingual SCCs was also shorter compared with maxillary SCCs (P = .0017). Furthermore, a significant association was identified between site and the presence of stromal CAFs (P = .025). On the basis of this retrospective study, evaluating the tumor stroma for CAFs in feline oral SCC biopsy specimens may be of potential prognostic value. © The Author(s) 2016.

Prognostic roles for fibroblast growth factor receptor family members in malignant peripheral nerve sheath tumor.

PubMed

Zhou, Wenya; Du, Xiaoling; Song, Fengju; Zheng, Hong; Chen, Kexin; Zhang, Wei; Yang, Jilong

2016-04-19

Malignant peripheral nerve sheath tumors (MPNST) are rare, highly malignant, and poorly understood sarcomas. The often poor outcome of MPNST highlights the necessity of identifying prognostic predictors for this aggressive sarcoma. Here, we investigate the role of fibroblast growth factor receptor (FGFR) family members in human MPNSTs. aCGH and bioinformatics analysis identified frequent amplification of the FGFR1 gene. FISH analysis revealed that 26.9% MPNST samples had amplification of FGFR1, with both focal and polysomy patterns observed. IHC identified that FGFR1 protein expression was positively correlated with FGFR1 gene amplification. High expression of FGFR1 protein was associated with better overall survival (OS) and was an independent prognostic predictor for OS of MPNST patients. Additionally, combined expression of FGFR1 and FGFR2 protein characterized a subtype of MPNST with better OS. FGFR4 protein was expressed 82.3% of MPNST samples, and was associated with poor disease-free survival. We performed microarray-based comparative genomic hybridization (aCGH) profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Medical University Cancer Institute and Hospital. Fluorescence in situ hybridization (FISH) was used to validate the gene amplification detected by aCGH analysis. Another cohort of 63 formalin-fixed paraffin-embedded MPNST samples (including 52 samples for FISH assay) was obtained to explore FGFR1, 2, 3, and 4 protein expression by immunohistochemical (IHC) analysis. Our integrated genomic and molecular studies provide evidence that FGFRs play different prognostic roles in MPNST.

Cluster analysis of spontaneous preterm birth phenotypes identifies potential associations among preterm birth mechanisms.

PubMed

Esplin, M Sean; Manuck, Tracy A; Varner, Michael W; Christensen, Bryce; Biggio, Joseph; Bukowski, Radek; Parry, Samuel; Zhang, Heping; Huang, Hao; Andrews, William; Saade, George; Sadovsky, Yoel; Reddy, Uma M; Ilekis, John

2015-09-01

We sought to use an innovative tool that is based on common biologic pathways to identify specific phenotypes among women with spontaneous preterm birth (SPTB) to enhance investigators' ability to identify and to highlight common mechanisms and underlying genetic factors that are responsible for SPTB. We performed a secondary analysis of a prospective case-control multicenter study of SPTB. All cases delivered a preterm singleton at SPTB ≤34.0 weeks' gestation. Each woman was assessed for the presence of underlying SPTB causes. A hierarchic cluster analysis was used to identify groups of women with homogeneous phenotypic profiles. One of the phenotypic clusters was selected for candidate gene association analysis with the use of VEGAS software. One thousand twenty-eight women with SPTB were assigned phenotypes. Hierarchic clustering of the phenotypes revealed 5 major clusters. Cluster 1 (n = 445) was characterized by maternal stress; cluster 2 (n = 294) was characterized by premature membrane rupture; cluster 3 (n = 120) was characterized by familial factors, and cluster 4 (n = 63) was characterized by maternal comorbidities. Cluster 5 (n = 106) was multifactorial and characterized by infection (INF), decidual hemorrhage (DH), and placental dysfunction (PD). These 3 phenotypes were correlated highly by χ(2) analysis (PD and DH, P < 2.2e-6; PD and INF, P = 6.2e-10; INF and DH, (P = .0036). Gene-based testing identified the INS (insulin) gene as significantly associated with cluster 3 of SPTB. We identified 5 major clusters of SPTB based on a phenotype tool and hierarch clustering. There was significant correlation between several of the phenotypes. The INS gene was associated with familial factors that were underlying SPTB. Copyright © 2015 Elsevier Inc. All rights reserved.

Genome-wide methylation profiling identifies an essential role of reactive oxygen species in pediatric glioblastoma multiforme and validates a methylome specific for H3 histone family 3A with absence of G-CIMP/isocitrate dehydrogenase 1 mutation

PubMed Central

Jha, Prerana; Pia Patric, Irene Rosita; Shukla, Sudhanshu; Pathak, Pankaj; Pal, Jagriti; Sharma, Vikas; Thinagararanjan, Sivaarumugam; Santosh, Vani; Suri, Vaishali; Sharma, Mehar Chand; Arivazhagan, Arimappamagan; Suri, Ashish; Gupta, Deepak; Somasundaram, Kumaravel; Sarkar, Chitra

2014-01-01

Background Pediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH)1 mutation with a DNA methylation signature. The present study aims to validate these findings in an independent cohort of pediatric GBM, compare it with adult GBM, and evaluate the involvement of important functionally altered pathways. Methods Genome-wide methylation profiling of 21 pediatric GBM cases was done and compared with adult GBM data (GSE22867). We performed gene mutation analysis of IDH1 and H3 histone family 3A (H3F3A), status evaluation of glioma cytosine–phosphate–guanine island methylator phenotype (G-CIMP), and Gene Ontology analysis. Experimental evaluation of reactive oxygen species (ROS) association was also done. Results Distinct differences were noted between methylomes of pediatric and adult GBM. Pediatric GBM was characterized by 94 hypermethylated and 1206 hypomethylated cytosine–phosphate–guanine (CpG) islands, with 3 distinct clusters, having a trend to prognostic correlation. Interestingly, none of the pediatric GBM cases showed G-CIMP/IDH1 mutation. Gene Ontology analysis identified ROS association in pediatric GBM, which was experimentally validated. H3F3A mutants (36.4%; all K27M) harbored distinct methylomes and showed enrichment of processes related to neuronal development, differentiation, and cell-fate commitment. Conclusions Our study confirms that pediatric GBM has a distinct methylome compared with that of adults. Presence of distinct clusters and an H3F3A mutation–specific methylome indicate existence of epigenetic subgroups within pediatric GBM. Absence of IDH1/G-CIMP status further indicates that findings in adult GBM cannot be simply extrapolated to pediatric GBM and that there is a strong need for identification of separate prognostic markers. A possible role of ROS in pediatric GBM pathogenesis is demonstrated for the first time and needs further evaluation. PMID:24997139

Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes

PubMed Central

Sandes, Alex F.; Yamamoto, Mihoko; Matarraz, Sergio; Chauffaille, Maria de Lourdes L.F.; Quijano, Sandra; López, Antonio; Oguro, Tsutomu; Kimura, Eliza Y. S.; Orfao, Alberto

2012-01-01

Background Multiparameter flow cytometric analysis of bone marrow and peripheral blood cells has proven to be of help in the diagnostic workup of myelodysplastic syndromes. However, the usefulness of flow cytometry for the detection of megakaryocytic and platelet dysplasia has not yet been investigated. The aim of this pilot study was to evaluate by flow cytometry the diagnostic and prognostic value of platelet dysplasia in myelodysplastic syndromes. Design and Methods We investigated the pattern of expression of distinct surface glycoproteins on peripheral blood platelets from a series of 44 myelodysplastic syndrome patients, 20 healthy subjects and 19 patients with platelet alterations associated to disease conditions other than myelodysplastic syndromes. Quantitative expression of CD31, CD34, CD36, CD41a, CD41b, CD42a, CD42b and CD61 glycoproteins together with the PAC-1, CD62-P, fibrinogen and CD63 platelet activation-associated markers and platelet light scatter properties were systematically evaluated. Results Overall, flow cytometry identified multiple immunophenotypic abnormalities on platelets of myelodysplastic syndrome patients, including altered light scatter characteristics, over-and under expression of specific platelet glycoproteins and asynchronous expression of CD34; decreased expression of CD36 (n=5), CD42a (n=1) and CD61 (n=2), together with reactivity for CD34 (n=1) were only observed among myelodysplastic syndrome cases, while other alterations were also found in other platelet disorders. Based on the overall platelet alterations detected for each patient, an immunophenotypic score was built which identified a subgroup of myelodysplastic syndrome patients with a high rate of moderate to severe alterations (score>1.5; n=16) who more frequently showed thrombocytopenia, megakaryocytic dysplasia and high-risk disease, together with a shorter overall survival. Conclusions Our results show the presence of altered phenotypes by flow cytometry on platelets from around half of the myelodysplastic syndrome patients studied. If confirmed in larger series of patients, these findings may help refine the diagnostic and prognostic assessment of this group of disorders. PMID:22271903

Targeting of hyperactivated mTOR signaling in high-risk acute lymphoblastic leukemia in a pre-clinical model.

PubMed

Hasan, Md Nabiul; Queudeville, Manon; Trentin, Luca; Eckhoff, Sarah Mirjam; Bronzini, Ilaria; Palmi, Chiara; Barth, Thomas; Cazzaniga, Giovanni; te Kronnie, Geertruy; Debatin, Klaus-Michael; Meyer, Lüder Hinrich

2015-01-30

Despite increasingly successful treatment of pediatric ALL, up to 20% of patients encounter relapse. By current biomarkers, the majority of relapse patients is initially not identified indicating the need for prognostic and therapeutic targets reflecting leukemia biology. We previously described that rapid engraftment of patient ALL cells transplanted onto NOD/SCID mice (short time to leukemia, TTLshort) is indicative of early patient relapse. Gene expression profiling identified genes coding for molecules involved in mTOR signaling to be associated with TTLshort/early relapse leukemia. Here, we now functionally address mTOR signaling activity in primograft ALL samples and evaluate mTOR pathway inhibition as novel treatment strategy for high-risk ALL ex vivo and in vivo. By analysis of S6-phosphorylation downstream of mTOR, increased mTOR activation was found in TTLshort/high-risk ALL, which was effectively abrogated by mTOR inhibitors resulting in decreased leukemia proliferation and growth. In a preclinical setting treating individual patient-derived ALL in vivo, mTOR inhibition alone, and even more pronounced together with conventional remission induction therapy, significantly delayed post-treatment leukemia reoccurrence in TTLshort/high-risk ALL. Thus, the TTLshort phenotype is functionally characterized by hyperactivated mTOR signaling and can effectively be targeted ex vivo and in vivo providing a novel therapeutic strategy for high-risk ALL.

Cytogenetic Profile of Moroccan Pediatric Acute Lymphoblastic Leukemia: Analysis of 155 Cases With a Review of the Literature.

PubMed

Chebihi, Zahra Takki; Belkhayat, Aziza; Chadli, Elbekkay; Hilal, Latifa; Skhoun, Hanaa; Hessissen, Laila; El Khorassani, Mohamed; El Kababri, Maria; Kili, Amina; Khattab, Mohammed; Bakri, Youssef; Dakka, Nadia

2018-04-25

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, with a peak incidence at 2 to 3 years of age and accounting for almost 30% of all cancers in this age group. It is well established that the identification of cytogenetic abnormalities is highly relevant for the prognosis of and therapeutic decisions in ALL. The purpose of the present study was to define the frequency of recurrent chromosomal abnormalities of ALL in Moroccan patients referred exclusively to the BIOLAB Laboratory of the Children's Hospital of Rabat during a 4-year period and compare our findings to the reported data. We performed conventional karyotyping of 155 ALL cases, with a successful cell culture rate of 94%. We identified chromosomal abnormalities in 66% of the total studied cases, of which 70% revealed important recurrent abnormalities with high prognostic value, such as hyperdiploidy, hypodiploidy, t(9;22), t(8;14), t(1;19), and MLL rearrangements. In total agreement with the reported data, most of the patients (56%) in the present study were aged 1 to 5 years, with a male predominance, and B-ALL was the most common blast phenotype (85%). The frequency of most chromosomal rearrangements successfully identified in our study and their lineage correlated with those reported in the published data. Copyright © 2018 Elsevier Inc. All rights reserved.

Acute lymphoblastic leukemia in children and adolescents: prognostic factors and analysis of survival

PubMed Central

Lustosa de Sousa, Daniel Willian; de Almeida Ferreira, Francisco Valdeci; Cavalcante Félix, Francisco Helder; de Oliveira Lopes, Marcos Vinicios

2015-01-01

Objective To describe the clinical and laboratory features of children and adolescents with acute lymphoblastic leukemia treated at three referral centers in Ceará and evaluate prognostic factors for survival, including age, gender, presenting white blood cell count, immunophenotype, DNA index and early response to treatment. Methods Seventy-six under 19-year-old patients with newly diagnosed acute lymphoblastic leukemia treated with the Grupo Brasileiro de Tratamento de Leucemia da Infância – acute lymphoblastic leukemia-93 and -99 protocols between September 2007 and December 2009 were analyzed. The diagnosis was based on cytological, immunophenotypic and cytogenetic criteria. Associations between variables, prognostic factors and response to treatment were analyzed using the chi-square test and Fisher's exact test. Overall and event-free survival were estimated by Kaplan–Meier analysis and compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors. Results The average age at diagnosis was 6.3 ± 0.5 years and males were predominant (65%). The most frequently observed clinical features were hepatomegaly, splenomegaly and lymphadenopathy. Central nervous system involvement and mediastinal enlargement occurred in 6.6% and 11.8%, respectively. B-acute lymphoblastic leukemia was more common (89.5%) than T-acute lymphoblastic leukemia. A DNA index >1.16 was found in 19% of patients and was associated with favorable prognosis. On Day 8 of induction therapy, 95% of the patients had lymphoblast counts <1000/μL and white blood cell counts <5.0 × 109/L. The remission induction rate was 95%, the induction mortality rate was 2.6% and overall survival was 72%. Conclusion The prognostic factors identified are compatible with the literature. The 5-year overall and event-free survival rates were lower than those reported for developed countries. As shown by the multivariate analysis, age and baseline white blood cell count were independent prognostic factors. PMID:26190424

Hypertrophic Cardiomyopathy from A to Z: Genetics, Pathophysiology, Imaging, and Management.

PubMed

Baxi, Ameya Jagdish; Restrepo, Carlos S; Vargas, Daniel; Marmol-Velez, Alejandro; Ocazionez, Daniel; Murillo, Horacio

2016-01-01

Hypertrophic cardiomyopathy (HCM) is a heterogeneous group of diseases related to sarcomere gene mutations exhibiting heterogeneous phenotypes with an autosomal dominant mendelian pattern of inheritance. The disorder is characterized by diverse phenotypic expressions and variable natural progression, which may range from dyspnea and/or syncope to sudden cardiac death. It is found across all racial groups and is associated with left ventricular hypertrophy in the absence of another systemic or cardiac disease. The management of HCM is based on a thorough understanding of the underlying morphology, pathophysiology, and clinical course. Imaging findings of HCM mirror the variable expressivity and penetrance heterogeneity, with the added advantage of diagnosis even in cases where a specific mutation may not yet be found. The diagnostic information obtained from imaging varies depending on the specific stage of HCM-phenotype manifestation, including the prehypertrophic, hypertrophic, and later stages of adverse remodeling into the burned-out phase of overt heart failure. However, subtle or obvious, these imaging findings become critical components in diagnosis, management, and follow-up of HCM patients. Although diagnosis of HCM traditionally relies on clinical assessment and transthoracic echocardiography, recent studies have demonstrated increased utility of multidetector computed tomography (CT) and particularly cardiac magnetic resonance (MR) imaging in diagnosis, phenotype differentiation, therapeutic planning, and prognostication. In this article, we provide an overview of the genetics, pathophysiology, and clinical manifestations of HCM, with the spectrum of imaging findings at MR imaging and CT and their contribution in diagnosis, risk stratification, and therapy. (©)RSNA, 2016.

Motor phenotype and magnetic resonance measures of basal ganglia iron levels in Parkinson's disease☆

PubMed Central

Bunzeck, Nico; Singh-Curry, Victoria; Eckart, Cindy; Weiskopf, Nikolaus; Perry, Richard J.; Bain, Peter G.; Düzel, Emrah; Husain, Masud

2013-01-01

Background In Parkinson's disease the degree of motor impairment can be classified with respect to tremor dominant and akinetic rigid features. While tremor dominance and akinetic rigidity might represent two ends of a continuum rather than discrete entities, it would be important to have non-invasive markers of any biological differences between them in vivo, to assess disease trajectories and response to treatment, as well as providing insights into the underlying mechanisms contributing to heterogeneity within the Parkinson's disease population. Methods Here, we used magnetic resonance imaging to examine whether Parkinson's disease patients exhibit structural changes within the basal ganglia that might relate to motor phenotype. Specifically, we examined volumes of basal ganglia regions, as well as transverse relaxation rate (a putative marker of iron load) and magnetization transfer saturation (considered to index structural integrity) within these regions in 40 individuals. Results We found decreased volume and reduced magnetization transfer within the substantia nigra in Parkinson's disease patients compared to healthy controls. Importantly, there was a positive correlation between tremulous motor phenotype and transverse relaxation rate (reflecting iron load) within the putamen, caudate and thalamus. Conclusions Our findings suggest that akinetic rigid and tremor dominant symptoms of Parkinson's disease might be differentiated on the basis of the transverse relaxation rate within specific basal ganglia structures. Moreover, they suggest that iron load within the basal ganglia makes an important contribution to motor phenotype, a key prognostic indicator of disease progression in Parkinson's disease. PMID:24025315

Isolated v-lesion represents a benign phenotype of vascular rejection of the kidney allograft- a retrospective study.

PubMed

Novotny, Marek; Hruba, Petra; Vichova, Petra; Maluskova, Jana; Honsova, Eva; Viklicky, Ondrej; Wohlfahrtova, Mariana

2018-05-31

While the detrimental impact of the humoral acute vascular rejection (AVR) phenotype is recognized, the prognostic significance of isolated v-lesion (IV) remains unclear. In this retrospective single-centre study, AVR was found in 98 out of 1015 patients (9.7%) who had undergone kidney transplantation in 2010-2014, with donor-specific antibodies (DSA) evaluated in all of them. The outcome of four AVR phenotypes was evaluated during median follow-up of 59 months; in 25 patients with IV, 18 with T cell-mediated vascular rejection (TCMRV), 19 with antibody-mediated vascular rejection (AMRV) and 36 with suspected antibody-mediated rejection (sAMRV). AVR was diagnosed mainly by for-cause biopsy (81%) early after transplantation (median 19 POD) and appeared as mild grade intimal arteritis. IV occurred in low sensitized patients after the first transplantation (96%) in the absence of DSA. IV responded satisfactorily to treatment (88%), showed no persistence of rejection in surveillance biopsy, had stable graft function, minimal proteinuria and excellent DCGS (96%). Contrary to that, Kaplan-Meier estimate of 3-year DCGS of AMRV was 66% (log rank=0.0004). Early IV represents a benign phenotype of AVR with a favourable outcome. This study prompts further research to evaluate the nature of IV before considering any change in the classification and management. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Lifecycle Prognostics Architecture for Selected High-Cost Active Components

DOE Office of Scientific and Technical Information (OSTI.GOV)

N. Lybeck; B. Pham; M. Tawfik

There are an extensive body of knowledge and some commercial products available for calculating prognostics, remaining useful life, and damage index parameters. The application of these technologies within the nuclear power community is still in its infancy. Online monitoring and condition-based maintenance is seeing increasing acceptance and deployment, and these activities provide the technological bases for expanding to add predictive/prognostics capabilities. In looking to deploy prognostics there are three key aspects of systems that are presented and discussed: (1) component/system/structure selection, (2) prognostic algorithms, and (3) prognostics architectures. Criteria are presented for component selection: feasibility, failure probability, consequences of failure,more » and benefits of the prognostics and health management (PHM) system. The basis and methods commonly used for prognostics algorithms are reviewed and summarized. Criteria for evaluating PHM architectures are presented: open, modular architecture; platform independence; graphical user interface for system development and/or results viewing; web enabled tools; scalability; and standards compatibility. Thirteen software products were identified and discussed in the context of being potentially useful for deployment in a PHM program applied to systems in a nuclear power plant (NPP). These products were evaluated by using information available from company websites, product brochures, fact sheets, scholarly publications, and direct communication with vendors. The thirteen products were classified into four groups of software: (1) research tools, (2) PHM system development tools, (3) deployable architectures, and (4) peripheral tools. Eight software tools fell into the deployable architectures category. Of those eight, only two employ all six modules of a full PHM system. Five systems did not offer prognostic estimates, and one system employed the full health monitoring suite but lacked operations and maintenance support. Each product is briefly described in Appendix A. Selection of the most appropriate software package for a particular application will depend on the chosen component, system, or structure. Ongoing research will determine the most appropriate choices for a successful demonstration of PHM systems in aging NPPs.« less

Differential diagnosis of neuromyelitis optica spectrum disorders

PubMed Central

Kim, Sung-Min; Kim, Seong-Joon; Lee, Haeng Jin; Kuroda, Hiroshi; Palace, Jacqueline; Fujihara, Kazuo

2017-01-01

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disorder of the central nervous system (CNS) mostly manifesting as optic neuritis and/or myelitis, which are frequently recurrent/bilateral or longitudinally extensive, respectively. As the autoantibody to aquaporin-4 (AQP4-Ab) can mediate the pathogenesis of NMOSD, testing for the AQP4-Ab in serum of patients can play a crucial role in diagnosing NMOSD. Nevertheless, the differential diagnosis of NMOSD in clinical practice is often challenging despite the phenotypical and serological characteristics of the disease because: (1) diverse diseases with autoimmune, vascular, infectious, or neoplastic etiologies can mimic these phenotypes of NMOSD; (2) patients with NMOSD may only have limited clinical manifestations, especially in their early disease stages; (3) test results for AQP4-Ab can be affected by several factors such as assay methods, serologic status, disease stages, or types of treatment; (4) some patients with NMOSD do not have AQP4-Ab; and (5) test results for the AQP4-Ab may not be readily available for the acute management of patients. Despite some similarity in their phenotypes, these NMOSD and NMOSD-mimics are distinct from each other in their pathogenesis, prognosis, and most importantly treatment. Understanding the detailed clinical, serological, radiological, and prognostic differences of these diseases will improve the proper management as well as diagnosis of patients. PMID:28670343

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

PubMed Central

Martín-Martín, Lourdes; López, Antonio; Vidriales, Belén; Caballero, María Dolores; Rodrigues, António Silva; Ferreira, Silvia Inês; Lima, Margarida; Almeida, Sérgio; Valverde, Berta; Martínez, Pilar; Ferrer, Ana; Candeias, Jorge; Ruíz-Cabello, Francisco; Buadesa, Josefa Marco; Sempere, Amparo; Villamor, Neus

2015-01-01

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. PMID:26056082

Influence of arterial hypertension, type 2 diabetes and cardiovascular risk factors on ALS outcome: a population-based study.

PubMed

Moglia, Cristina; Calvo, Andrea; Canosa, Antonio; Bertuzzo, Davide; Cugnasco, Paolo; Solero, Luca; Grassano, Maurizio; Bersano, Enrica; Cammarosano, Stefania; Manera, Umberto; Pisano, Fabrizio; Mazzini, Letizia; Dalla Vecchia, Laura A; Mora, Gabriele; Chiò, Adriano

2017-11-01

To assess the prognostic influence of pre-morbid type 2 diabetes mellitus, arterial hypertension and cardiovascular (CV) risk profile on ALS phenotype and outcome in a population-based cohort of Italian patients. A total of 650 ALS patients from the Piemonte/Valle d'Aosta Register for ALS, incident in the 2007-2011 period, were recruited. Information about premorbid presence of type 2 diabetes mellitus, arterial hypertension was collected at the time of diagnosis. Patients' CV risk profile was calculated according to the Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice (JBS2). At the univariate analysis, the presence of pre-morbid arterial hypertension was associated with a higher age at onset of ALS and a shorter survival, and patients with a high CV risk profile had a worse prognosis than those with a low CV risk profile. The Cox multivariable analysis did not confirm such findings. Type 2 diabetes mellitus did not modify either the phenotype or the prognosis of ALS patients. This study performed on a large population-based cohort of ALS patients has demonstrated that arterial hypertension, type 2 diabetes and CV risk factors, calculated using the Framingham equation, do not influence ALS phenotype and prognosis.

Interactomic approach for evaluating nucleophosmin-binding proteins as biomarkers for Ewing's sarcoma.

PubMed

Haga, Ayako; Ogawara, Yoko; Kubota, Daisuke; Kitabayashi, Issay; Murakami, Yasufumi; Kondo, Tadashi

2013-06-01

Nucleophosmin (NPM) is a novel prognostic biomarker for Ewing's sarcoma. To evaluate the prognostic utility of NPM, we conducted an interactomic approach to characterize the NPM protein complex in Ewing's sarcoma cells. A gene suppression assay revealed that NPM promoted cell proliferation and the invasive properties of Ewing's sarcoma cells. FLAG-tag-based affinity purification coupled with liquid chromatography-tandem mass spectrometry identified 106 proteins in the NPM protein complex. The functional classification suggested that the NPM complex participates in critical biological events, including ribosome biogenesis, regulation of transcription and translation, and protein folding, that are mediated by these proteins. In addition to JAK1, a candidate prognostic biomarker for Ewing's sarcoma, the NPM complex, includes 11 proteins known as prognostic biomarkers for other malignancies. Meta-analysis of gene expression profiles of 32 patients with Ewing's sarcoma revealed that 6 of 106 were significantly and independently associated with survival period. These observations suggest a functional role as well as prognostic value of these NPM complex proteins in Ewing's sarcoma. Further, our study suggests the potential applications of interactomics in conjunction with meta-analysis for biomarker discovery. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Baseline prostate-specific antigen levels following treatment with abiraterone acetate as a prognostic factor in castration-resistant prostate cancer

PubMed Central

Hiroshige, Tasuku; Eguchi, Yoshiro; Yoshizumi, Osamu; Chikui, Katsuaki; Kumagai, Hisaji; Kawaguchi, Yoshihiro; Onishi, Rei; Hayashi, Tokumasa; Watanabe, Kouta; Mitani, Tomotaro; Saito, Koujiro; Igawa, Tsukasa

2018-01-01

The aim of the present study was to investigate the prognostic factors associated with progression-free survival (PFS) and overall survival (OS) times in patients with castration-resistant prostate cancer (CRPC) who received treatment with abiraterone acetate (AA) in routine clinical settings. A total of 93 patients treated with AA between September 2014 and February 2017 were selected and their medical records were analyzed retrospectively. The median PFS time of docetaxel (DTX)-naïve patients was 171 days, and that of post-DTX patients was 56 days. The OS time of DTX-naïve patients did not reach the median. The median OS time of post-DTX patients was 761 days. Multivariate analyses identified baseline prostate-specific antigen (PSA) level prior to treatment with AA and the PSA response rate as independent prognostic factors for PFS time, and baseline PSA prior to treatment with AA as the only independent prognostic factor for OS time. The results of the present study indicate that the baseline PSA level prior to treatment with AA is a notable prognostic factor in patients with CRPC. PMID:29725416

Baseline prostate-specific antigen levels following treatment with abiraterone acetate as a prognostic factor in castration-resistant prostate cancer.

PubMed

Hiroshige, Tasuku; Eguchi, Yoshiro; Yoshizumi, Osamu; Chikui, Katsuaki; Kumagai, Hisaji; Kawaguchi, Yoshihiro; Onishi, Rei; Hayashi, Tokumasa; Watanabe, Kouta; Mitani, Tomotaro; Saito, Koujiro; Igawa, Tsukasa

2018-05-01

The aim of the present study was to investigate the prognostic factors associated with progression-free survival (PFS) and overall survival (OS) times in patients with castration-resistant prostate cancer (CRPC) who received treatment with abiraterone acetate (AA) in routine clinical settings. A total of 93 patients treated with AA between September 2014 and February 2017 were selected and their medical records were analyzed retrospectively. The median PFS time of docetaxel (DTX)-naïve patients was 171 days, and that of post-DTX patients was 56 days. The OS time of DTX-naïve patients did not reach the median. The median OS time of post-DTX patients was 761 days. Multivariate analyses identified baseline prostate-specific antigen (PSA) level prior to treatment with AA and the PSA response rate as independent prognostic factors for PFS time, and baseline PSA prior to treatment with AA as the only independent prognostic factor for OS time. The results of the present study indicate that the baseline PSA level prior to treatment with AA is a notable prognostic factor in patients with CRPC.

[Prognostic factors of early breast cancer].

PubMed

Almagro, Elena; González, Cynthia S; Espinosa, Enrique

2016-02-19

Decision about the administration of adjuvant therapy for early breast cancer depends on the evaluation of prognostic factors. Lymph node status, tumor size and grade of differentiation are classical variables in this regard, and can be complemented by hormonal receptor status and HER2 expression. These factors can be combined into prognostic indexes to better estimate the risk of relapse or death. Other factors are less important. Gene profiles have emerged in recent years to identify low-risk patients who can forgo adjuvant chemotherapy. A number of profiles are available and can be used in selected cases. In the future, gene profiling will be used to select patients for treatment with new targeted therapies. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Nutritional prognostic scores in patients with hilar cholangiocarcinoma treated by percutaneous transhepatic biliary stenting combined with 125I seed intracavitary irradiation: A retrospective observational study.

PubMed

Cui, Peiyuan; Pang, Qing; Wang, Yong; Qian, Zhen; Hu, Xiaosi; Wang, Wei; Li, Zongkuang; Zhou, Lei; Man, Zhongran; Yang, Song; Jin, Hao; Liu, Huichun

2018-06-01

We mainly aimed to preliminarily explore the prognostic values of nutrition-based prognostic scores in patients with advanced hilar cholangiocarcinoma (HCCA).We retrospectively analyzed 73 cases of HCCA, who underwent percutaneous transhepatic biliary stenting (PTBS) combined with I seed intracavitary irradiation from November 2012 to April 2017 in our department. The postoperative changes of total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin (ALB) were observed. The preoperative clinical data were collected to calculate the nutrition-based scores, including controlling nutritional status (CONUT), C-reactive protein/albumin ratio (CAR), and prognostic nutritional index (PNI). Kaplan-Meier curve and Cox regression model were used for overall survival (OS) analyses.The serum levels of TBIL, DBIL, ALT, AST, and ALP significantly reduced, and ALB significantly increased at 1 month and 3 months postoperatively. The median survival time of the cohort was 12 months and the 1-year survival rate was 53.1%. Univariate analysis revealed that the statistically significant factors related to OS were CA19-9, TBIL, ALB, CONUT, and PNI. Multivariate analysis further identified CA19-9, CONUT, and PNI as independent prognostic factors.Nutrition-based prognostic scores, CONUT and PNI in particular, can be used as predictors of survival in unresectable HCCA.

Neutrophils in critical illness.

PubMed

McDonald, Braedon

2018-03-01

During critical illness, dramatic alterations in neutrophil biology are observed including abnormalities of granulopoeisis and lifespan, cell trafficking and antimicrobial effector functions. As a result, neutrophils transition from powerful antimicrobial protectors into dangerous mediators of tissue injury and organ dysfunction. In this article, the role of neutrophils in the pathogenesis of critical illness (sepsis, trauma, burns and others) will be explored, including pathological changes to neutrophil function during critical illness and the utility of monitoring aspects of the neutrophil phenotype as biomarkers for diagnosis and prognostication. Lastly, we review findings from clinical trials of therapies that target the harmful effects of neutrophils, providing a bench-to-bedside perspective on neutrophils in critical illness.

Electromechanical actuators affected by multiple failures: Prognostic method based on spectral analysis techniques

NASA Astrophysics Data System (ADS)

Belmonte, D.; Vedova, M. D. L. Dalla; Ferro, C.; Maggiore, P.

2017-06-01

The proposal of prognostic algorithms able to identify precursors of incipient failures of primary flight command electromechanical actuators (EMA) is beneficial for the anticipation of the incoming failure: an early and correct interpretation of the failure degradation pattern, in fact, can trig an early alert of the maintenance crew, who can properly schedule the servomechanism replacement. An innovative prognostic model-based approach, able to recognize the EMA progressive degradations before his anomalous behaviors become critical, is proposed: the Fault Detection and Identification (FDI) of the considered incipient failures is performed analyzing proper system operational parameters, able to put in evidence the corresponding degradation path, by means of a numerical algorithm based on spectral analysis techniques. Subsequently, these operational parameters will be correlated with the actual EMA health condition by means of failure maps created by a reference monitoring model-based algorithm. In this work, the proposed method has been tested in case of EMA affected by combined progressive failures: in particular, partial stator single phase turn to turn short-circuit and rotor static eccentricity are considered. In order to evaluate the prognostic method, a numerical test-bench has been conceived. Results show that the method exhibit adequate robustness and a high degree of confidence in the ability to early identify an eventual malfunctioning, minimizing the risk of fake alarms or unannounced failures.

Nomograms Predicting Progression-Free Survival, Overall Survival, and Pelvic Recurrence in Locally Advanced Cervical Cancer Developed From an Analysis of Identifiable Prognostic Factors in Patients From NRG Oncology/Gynecologic Oncology Group Randomized Trials of Chemoradiotherapy

PubMed Central

Rose, Peter G.; Java, James; Whitney, Charles W.; Stehman, Frederick B.; Lanciano, Rachelle; Thomas, Gillian M.; DiSilvestro, Paul A.

2015-01-01

Purpose To evaluate the prognostic factors in locally advanced cervical cancer limited to the pelvis and develop nomograms for 2-year progression-free survival (PFS), 5-year overall survival (OS), and pelvic recurrence. Patients and Methods We retrospectively reviewed 2,042 patients with locally advanced cervical carcinoma enrolled onto Gynecologic Oncology Group clinical trials of concurrent cisplatin-based chemotherapy and radiotherapy. Nomograms for 2-year PFS, five-year OS, and pelvic recurrence were created as visualizations of Cox proportional hazards regression models. The models were validated by bootstrap-corrected, relatively unbiased estimates of discrimination and calibration. Results Multivariable analysis identified prognostic factors including histology, race/ethnicity, performance status, tumor size, International Federation of Gynecology and Obstetrics stage, tumor grade, pelvic node status, and treatment with concurrent cisplatin-based chemotherapy. PFS, OS, and pelvic recurrence nomograms had bootstrap-corrected concordance indices of 0.62, 0.64, and 0.73, respectively, and were well calibrated. Conclusion Prognostic factors were used to develop nomograms for 2-year PFS, 5-year OS, and pelvic recurrence for locally advanced cervical cancer clinically limited to the pelvis treated with concurrent cisplatin-based chemotherapy and radiotherapy. These nomograms can be used to better estimate individual and collective outcomes. PMID:25732170

Updating and prospective validation of a prognostic model for high sickness absence.

PubMed

Roelen, C A M; Heymans, M W; Twisk, J W R; van Rhenen, W; Pallesen, S; Bjorvatn, B; Moen, B E; Magerøy, N

2015-01-01

To further develop and validate a Dutch prognostic model for high sickness absence (SA). Three-wave longitudinal cohort study of 2,059 Norwegian nurses. The Dutch prognostic model was used to predict high SA among Norwegian nurses at wave 2. Subsequently, the model was updated by adding person-related (age, gender, marital status, children at home, and coping strategies), health-related (BMI, physical activity, smoking, and caffeine and alcohol intake), and work-related (job satisfaction, job demands, decision latitude, social support at work, and both work-to-family and family-to-work spillover) variables. The updated model was then prospectively validated for predictions at wave 3. 1,557 (77 %) nurses had complete data at wave 2 and 1,342 (65 %) at wave 3. The risk of high SA was under-estimated by the Dutch model, but discrimination between high-risk and low-risk nurses was fair after re-calibration to the Norwegian data. Gender, marital status, BMI, physical activity, smoking, alcohol intake, job satisfaction, job demands, decision latitude, support at the workplace, and work-to-family spillover were identified as potential predictors of high SA. However, these predictors did not improve the model's discriminative ability, which remained fair at wave 3. The prognostic model correctly identifies 73 % of Norwegian nurses at risk of high SA, although additional predictors are needed before the model can be used to screen working populations for risk of high SA.

PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma

PubMed Central

Phillips, Joanna J.; Aranda, Derick; Ellison, David W.; Judkins, Alexander R.; Croul, Sidney E.; Brat, Daniel J.; Ligon, Keith L.; Horbinski, Craig; Venneti, Sriram; Zadeh, Gelareh; Santi, Mariarita; Zhou, Shengmei; Appin, Christina L.; Sioletic, Stefano; Sullivan, Lisa M.; Martinez-Lage, Maria; Robinson, Aaron E.; Yong, William H.; Cloughesy, Timothy; Lai, Albert; Phillips, Heidi S.; Marshall, Roxanne; Mueller, Sabine; Haas-Kogan, Daphne A.; Molinaro, Annette M.; Perry, Arie

2013-01-01

High-grade astrocytomas (HGAs), corresponding to WHO grades III (AA) and IV (GBM), are biologically aggressive and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non-amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and IDH1R132H mutation was a significant independent prognostic factor (p=0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs. PMID:23438035

Molecular pathways: targeting p21-activated kinase 1 signaling in cancer--opportunities, challenges, and limitations.

PubMed

Eswaran, Jeyanthy; Li, Da-Qiang; Shah, Anil; Kumar, Rakesh

2012-07-15

The evolution of cancer cells involves deregulation of highly regulated fundamental pathways that are central to normal cellular architecture and functions. p21-activated kinase 1 (PAK1) was initially identified as a downstream effector of the GTPases Rac and Cdc42. Subsequent studies uncovered a variety of new functions for this kinase in growth factor and steroid receptor signaling, cytoskeleton remodeling, cell survival, oncogenic transformation, and gene transcription, largely through systematic discovery of its direct, physiologically relevant substrates. PAK1 is widely upregulated in several human cancers, such as hormone-dependent cancer, and is intimately linked to tumor progression and therapeutic resistance. These exciting developments combined with the kinase-independent role of PAK1-centered phenotypic signaling in cancer cells elevated PAK1 as an attractive drug target. Structural and biochemical studies revealed the precise mechanism of PAK1 activation, offering the possibility to develop PAK1-targeted cancer therapeutic approaches. In addition, emerging reports suggest the potential of PAK1 and its specific phosphorylated substrates as cancer prognostic markers. Here, we summarize recent findings about the PAK1 molecular pathways in human cancer and discuss the current status of PAK1-targeted anticancer therapies.

Serrated adenocarcinoma morphology in colorectal mucinous adenocarcinoma is associated with improved patient survival

PubMed Central

Lee, Chung-Ta; Chow, Nan-Haw; Su, Pei-Fang; Ho, Chung-Liang; Tsai, Hung-Wen; Chen, Yi-Lin; Lin, Shao-Chieh; Lin, Bo-Wen; Lin, Peng-Chan; Lee, Jenq-Chang

2017-01-01

Colorectal mucinous adenocarcinoma (MAC) and serrated adenocarcinoma (SAC) share many characteristics, including right-side colon location, frequent mucin production, and various molecular features. This study examined the frequency of SAC morphology in MACs. We assessed the correlation of SAC morphology with clinicopathological parameters, molecular characteristics, and patient prognosis. Eighty-eight colorectal MACs were collected and reviewed for SAC morphology according to Makinen's criteria. We sequenced KRAS and BRAF, assessed CpG island methylator phenotype (CIMP) frequency, and analyzed DNA mismatch repair enzyme levels using immunohistochemistry in tumor samples. SAC morphology was observed in 38% of MACs, and was associated with proximal location (P=0.001), BRAF mutation (P=0.042), CIMP-positive status (P=0.023), and contiguous traditional serrated adenoma (P=0.019). Multivariate analysis revealed that MACs without both SAC morphology and CIMP-positive status exhibited 3.955 times greater risk of cancer relapse than MACs having both characteristics or either one (P=0.035). Our results show that two MAC groups with distinct features can be identified using Makinen's criteria, and suggest a favorable prognostic role for the serrated neoplastic pathway in colorectal MAC. PMID:28422723

LMTK3 expression in breast cancer: association with tumor phenotype and clinical outcome.

PubMed

Stebbing, Justin; Filipovic, Aleksandra; Ellis, Ian O; Green, Andrew R; D'Silva, Tanya Rapoz; Lenz, Heinz-Josef; Coombes, R Charles; Wang, Tingting; Lee, Soo-Chin; Giamas, Georgios

2012-04-01

Interactions between kinases and the estrogen receptor α (ERα) are thought to be a critical signaling pathway in the majority of human breast cancers. We have recently identified a previously uncharacterized molecule, lemur tyrosine kinase-3 (LMTK3) as a prognostic and predictive oncogenic ERα regulator with a central role in endocrine resistance. Unusually this protein has undergone Darwinian positive selection between Chimpanzees and humans suggesting it may contribute to human susceptibility to ERα-positive tumors. Using over 600 European primary breast cancer cases, we wished to establish tumor characteristics associated with both cytoplasmic and nuclear LMTK3 expression, and then externally validate our observed European clinical outcomes with samples from Asian individuals receiving chemotherapy. Both nuclear and cytoplasmic expression correlated with tumor grade (P < 0.001) and in the Asian cohort, independent blinded analyses demonstrated that high basal LMTK3 expression was associated with advanced stage of primary breast cancers as well as decreased overall (P = 0.03) and disease-free survival (P = 0.006). In summary, higher LMTK3 expression is associated with more aggressive cancers. These data support our previous findings and suggest LMTK3 expression may be a reliable new biomarker in breast cancer.

Identifying pathological biomarkers: histochemistry still ranks high in the omics era

PubMed Central

Pellicciari, C.; Malatesta, M.

2011-01-01

In recent years, omic analyses have been proposed as possible approaches to diagnosis, in particular for tumours, as they should be able to provide quantitative tools to detect and measure abnormalities in gene and protein expression, through the evaluation of transcription and translation products in the abnormal vs normal tissues. Unfortunately, this approach proved to be much less powerful than expected, due to both intrinsic technical limits and the nature itself of the pathological tissues to be investigated, the heterogeneity deriving from polyclonality and tissue phenotype variability between patients being a major limiting factor in the search for unique omic biomarkers. Especially in the last few years, the application of refined techniques for investigating gene expression in situ has greatly increased the diagnostic/prognostic potential of histochemistry, while the progress in light microscopy technology and in the methods for imaging molecules in vivo have provided valuable tools for elucidating the molecular events and the basic mechanisms leading to a pathological condition. Histochemical techniques thus remain irreplaceable in pathologist's armamentarium, and it may be expected that even in the future histochemistry will keep a leading position among the methodological approaches for clinical pathology. PMID:22297448

Epidemiology, demographic characteristics and prognostic predictors of ulcerative colitis

PubMed Central

da Silva, Bruno César; Lyra, Andre Castro; Rocha, Raquel; Santana, Genoile Oliveira

2014-01-01

Ulcerative colitis (UC) is a chronic disease characterized by diffuse inflammation of the mucosa of the colon and rectum. The hallmark clinical symptom of UC is bloody diarrhea. The clinical course is marked by exacerbations and remissions, which may occur spontaneously or in response to treatment changes or intercurrent illnesses. UC is most commonly diagnosed in late adolescence or early adulthood, but it can occur at any age. The incidence of UC has increased worldwide over recent decades, especially in developing nations. In contrast, during this period, therapeutic advances have improved the life expectancy of patients, and there has been a decrease in the mortality rate over time. It is important to emphasize that there is considerable variability in the phenotypic presentation of UC. Within this context, certain clinical and demographic characteristics are useful in identifying patients who tend to have more severe evolution of the disease and a poor prognosis. In this group of patients, better clinical surveillance and more intensive therapy may change the natural course of the disease. The aim of this article was to review the epidemiology and demographic characteristics of UC and the factors that may be associated with its clinical prognosis. PMID:25071340

Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

PubMed Central

Abbate, Carlo; Trimarchi, Pietro Davide; Inglese, Silvia; Viti, Niccolò; Cantatore, Alessandra; De Agostini, Lisa; Pirri, Federico; Marino, Lorenza; Bagarolo, Renzo

2014-01-01

Objective. We describe a case of dementia with Lewy bodies (DLB) that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI-) DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS). The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder. PMID:24868122

RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

PubMed Central

Catenacci, Daniel VT; Cervantes, Gustavo; Yala, Soheil; Nelson, Erik A; El-Hashani, Essam; Kanteti, Rajani; El Dinali, Mohamed; Hasina, Rifat; Brägelmann, Johannes; Seiwert, Tanguy; Sanicola, Michele; Henderson, Les; Grushko, Tatyana A; Olopade, Olufunmilayo; Karrison, Theodore; Bang, Yung-Jue; Ho Kim, Woo; Tretiakova, Maria; Vokes, Everett; Frank, David A; Kindler, Hedy L; Huet, Heather

2011-01-01

RON (MST1R) is one of two members of the MET receptor tyrosine kinase family, along with parent receptor MET. RON has a putative role in several cancers, but its expression and function is poorly characterized in gastroesophageal adenocarcinoma. A recognized functional role of MET tyrosine kinase in gastroesophageal cancer has led to early phase clinical trials using MET inhibitors, with unimpressive results. Therefore, the role of RON in gastroesophageal cancer, as well as its role in cooperative signaling with MET and as a mechanism of resistance to MET inhibition, was studied in gastroesophageal tissues and cell lines. By IHC, RON was highly overexpressed in 74% of gastroesophageal samples (n = 94) and overexpression was prognostic of poor survival (p = 0.008); RON and MET co-expression occurred in 43% of samples and was prognostic of worst survival (p = 0.03). High MST1R gene copy number by quantitative polymerase chain reaction and confirmed by fluorescence in situ hybridization and/or array comparative genomic hybridization, was seen in 35.5% (16/45) of cases. High MST1R gene copy number correlated with poor survival (p = 0.01), and was associated with high MET and ERBB2 gene copy number. a novel somatic MST1R juxtamembrane mutation R1018G was found in 11% of samples. RON signaling was functional in cell lines, activating downstream effector STAT3, and resulted in increased viability over controls. RON and MET co-stimulation assays led to enhanced malignant phenotypes over stimulation of either receptor alone. Growth inhibition as evidenced by viability and apoptosis assays was optimal using novel blocking monoclonal antibodies to both ROn and MET, versus either alone. SU11274, a classic MET small molecule tyrosine kinase inhibitor, blocked signaling of both receptors and proved synergistic when combined with STAT3 inhibition (combination index <1). These preclinical studies define RON as an important novel prognostic marker and therapeutic target for gastroesophageal cancer warranting further investigation. PMID:21543897

Rhabdoid and Undifferentiated Phenotype in Renal Cell Carcinoma: Analysis of 32 Cases Indicating a Distinctive Common Pathway of Dedifferentiation Frequently Associated With SWI/SNF Complex Deficiency.

PubMed

Agaimy, Abbas; Cheng, Liang; Egevad, Lars; Feyerabend, Bernd; Hes, Ondřej; Keck, Bastian; Pizzolitto, Stefano; Sioletic, Stefano; Wullich, Bernd; Hartmann, Arndt

2017-02-01

Undifferentiated (anaplastic) and rhabdoid cell features are increasingly recognized as adverse prognostic findings in renal cell carcinoma (RCC), but their molecular pathogenesis has not been studied sufficiently. Recent studies identified alterations in the Switch Sucrose nonfermentable (SWI/SNF) chromatin remodeling complex as molecular mechanisms underlying dedifferentiation and rhabdoid features in carcinomas of different organs. We herein have analyzed 32 undifferentiated RCCs having in common an undifferentiated (anaplastic) phenotype, prominent rhabdoid features, or both, irrespective of the presence or absence of conventional RCC component. Cases were stained with 6 SWI/SNF pathway members (SMARCB1, SMARCA2, SMARCA4, ARID1A, SMARCC1, and SMARCC2) in addition to conventional RCC markers. Patients were 20 males and 12 females aged 32 to 85 years (mean, 59). A total of 22/27 patients with known stage presented with ≥pT3. A differentiated component varying from microscopic to major component was detected in 20/32 cases (16 clear cell and 2 cases each chromophobe and papillary RCC). The undifferentiated component varied from rhabdoid dyscohesive cells to large epithelioid to small monotonous anaplastic cells. Variable loss of at least 1 SWI/SNF complex subunit was noted in the undifferentiated/rhabdoid component of 21/32 cases (65%) compared with intact or reduced expression in the differentiated component. A total of 15/17 patients (88%) with follow-up died of metastatic disease (mostly within 1 y). Only 2 patients were disease free at last follow-up (1 and 6 y). No difference in survival, age distribution, or sex was observed between the SWI/SNF-deficient and the SWI/SNF-intact group. This is the first study exploring the role of SWI/SNF deficiency as a potential mechanism underlying undifferentiated and rhabdoid phenotype in RCC. Our results highlight the association between the aggressive rhabdoid phenotype and the SWI/SNF complex deficiency, consistent with studies on similar neoplasms in other organs. Thorough sampling of such tumors that are usually huge and locally advanced is necessary for recognizing the clone of origin and hence for proper subtyping and also for differentiating them from undifferentiated urothelial carcinoma.

CD44 Staining of Cancer Stem-Like Cells Is Influenced by Down-Regulation of CD44 Variant Isoforms and Up-Regulation of the Standard CD44 Isoform in the Population of Cells That Have Undergone Epithelial-to-Mesenchymal Transition

PubMed Central

Biddle, Adrian; Gammon, Luke; Fazil, Bilal; Mackenzie, Ian C.

2013-01-01

CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumours, and we have previously demonstrated the existence of two different CD44high cancer stem-like cell populations in squamous cell carcinoma, one having undergone epithelial-to-mesenchymal transition and the other maintaining an epithelial phenotype. Alternative splicing of CD44 variant exons generates a great many isoforms, and it is not known which isoforms are expressed on the surface of the two different cancer stem-like cell phenotypes. Here, we demonstrate that cancer stem-like cells with an epithelial phenotype predominantly express isoforms containing the variant exons, whereas the cancer stem-like cells that have undergone an epithelial-to-mesenchymal transition down-regulate these variant isoforms and up-regulate expression of the standard CD44 isoform that contains no variant exons. In addition, we find that enzymatic treatments used to dissociate cells from tissue culture or fresh tumour specimens cause destruction of variant CD44 isoforms at the cell surface whereas expression of the standard CD44 isoform is preserved. This results in enrichment within the CD44high population of cancer stem-like cells that have undergone an epithelial-to-mesenchymal transition and depletion from the CD44high population of cancer stem-like cells that maintain an epithelial phenotype, and therefore greatly effects the characteristics of any cancer stem-like cell population isolated based on expression of CD44. As well as effecting the CD44high population, enzymatic treatment also reduces the percentage of the total epithelial cancer cell population staining CD44-positive, with potential implications for studies that aim to use CD44-positive staining as a prognostic indicator. Analyses of the properties of cancer stem-like cells are largely dependent on the ability to accurately identify and assay these populations. It is therefore critical that consideration be given to use of multiple cancer stem-like cell markers and suitable procedures for cell isolation in order that the correct populations are assayed. PMID:23437366

Prognostic value of lymph node ratio in head and neck squamous cell carcinoma.

PubMed

Talmi, Yoav P; Takes, Robert P; Alon, Eran E; Nixon, Iain J; López, Fernando; de Bree, Remco; Rodrigo, Juan P; Shaha, Ashok R; Halmos, Gyorgy B; Rinaldo, Alessandra; Ferlito, Alfio

2018-05-01

Lymph node ratio (LNR) is increasingly reported as a potential prognostic tool. The purpose of this review was to analyze the available literature on the prognostic significance of LNR in head and neck squamous cell carcinoma (HNSCC). A PubMed internet search was performed and articles meeting selection criteria were reviewed. Twenty-eight studies were identified in the literature dealing with the prognostic value of LNR. The published results are variable with a range of cutoff values of LNR associated with prognosis (overall survival [OS] and/or disease-specific survival [DSS]) between 0.02 and 0.20, with an average of 0.09. The LNR is reported to be of value in assessing prognosis in the patients with HNSCC. Although it is easy to calculate and could be considered in the staging of these patients, the currently available evidence in the literature does not yet provide a solid base for implementation. © 2018 Wiley Periodicals, Inc.

An Assessment of Integrated Health Management (IHM) Frameworks

DOE Office of Scientific and Technical Information (OSTI.GOV)

N. Lybeck; M. Tawfik; L. Bond

In order to meet the ever increasing demand for energy, the United States nuclear industry is turning to life extension of existing nuclear power plants (NPPs). Economically ensuring the safe, secure, and reliable operation of aging nuclear power plants presents many challenges. The 2009 Light Water Reactor Sustainability Workshop identified online monitoring of active and structural components as essential to the better understanding and management of the challenges posed by aging nuclear power plants. Additionally, there is increasing adoption of condition-based maintenance (CBM) for active components in NPPs. These techniques provide a foundation upon which a variety of advanced onlinemore » surveillance, diagnostic, and prognostic techniques can be deployed to continuously monitor and assess the health of NPP systems and components. The next step in the development of advanced online monitoring is to move beyond CBM to estimating the remaining useful life of active components using prognostic tools. Deployment of prognostic health management (PHM) on the scale of a NPP requires the use of an integrated health management (IHM) framework - a software product (or suite of products) used to manage the necessary elements needed for a complete implementation of online monitoring and prognostics. This paper provides a thoughtful look at the desirable functions and features of IHM architectures. A full PHM system involves several modules, including data acquisition, system modeling, fault detection, fault diagnostics, system prognostics, and advisory generation (operations and maintenance planning). The standards applicable to PHM applications are indentified and summarized. A list of evaluation criteria for PHM software products, developed to ensure scalability of the toolset to an environment with the complexity of a NPP, is presented. Fourteen commercially available PHM software products are identified and classified into four groups: research tools, PHM system development tools, deployable architectures, and peripheral tools.« less

Prognostic value of circulating microRNAs in upper tract urinary carcinoma

PubMed Central

Ingelmo-Torres, Mercedes; Lozano, Juan José; Capitán, David; Alcaraz, Antonio; Mengual, Lourdes

2018-01-01

The identification of upper tract urinary carcinoma (UTUC) prognostic biomarkers is urgently needed to predict tumour progression. This study aimed to identify serum microRNAs (miRNAs) that may be useful as minimally invasive predictive biomarkers of tumour progression and survival in UTUC patients. To this end, 33 UTUC patients who underwent radical nephroureterectomy at the Hospital Clinic of Barcelona were prospectively included. Expression of 800 miRNAs was evaluated in serum samples from these patients using nCounter® miRNA Expression Assays. The study was divided into an initial discovery phase (n=12) and a validation phase (n=21). Cox regression analysis was used for survival analysis. The median follow-up (range) of the series was 42 months (9-100 months). In the discovery phase, 38 differentially expressed miRNAs were identified between progressing and non-progressing UTUC patients (p<0.05). Validation of these 38 miRNAs in an independent set of UTUC patients confirmed the differential expression in 18 of them (p<0.05). Cox Regression analysis showed miR-151b and pathological stage as significant prognostic factors for tumour progression (HR=0.33, p<0.001 and HR=2.62, p=0.006, respectively) and cancer specific survival (HR=0.25, p<0.001 and HR=3.98, p=0.003, respectively). Survival curves revealed that miR-151b is able to discriminate between two groups of UTUC patients with a highly significant different probability of tumour progression (p=0.006) and cancer specific survival (p=0.034). Although the data needs to be externally validated, miRNA analysis in serum appears to be a valuable prognostic tool in UTUC patients. Particularly, differential expression of miR-151b in serum may serve as a minimally invasive prognostic tool in UTUC. PMID:29682178

Tumor-infiltrating Neutrophils is Prognostic and Predictive for Postoperative Adjuvant Chemotherapy Benefit in Patients With Gastric Cancer.

PubMed

Zhang, Heng; Liu, Hao; Shen, Zhenbin; Lin, Chao; Wang, Xuefei; Qin, Jing; Qin, Xinyu; Xu, Jiejie; Sun, Yihong

2018-02-01

This study was aimed to investigate the prognostic value of tumor-infiltrating neutrophils (TINs) and to generate a predictive model to refine postoperative risk stratification system for patients with gastric cancer. TIN presents in various malignant tumors, but its clinical significance in gastric cancer remains obscure. The study enrolled 3 independent sets of patients with gastric cancer from 2 institutional medical centers of China. TIN was estimated by immunohistochemical staining of CD66b, and its relationship with clinicopathological features and clinical outcomes were evaluated. Prognostic accuracies were evaluated by C-index and Akaike information criterion. TINs in gastric cancer tissues ranged from 0 to 192 cells/high magnification filed (HPF), 0 to 117 cells/HPF, and 0 to 142 cells/HPF in the training, testing, and validation sets, respectively. TINs were negatively correlated with lymph node classification (P = 0.007, P = 0.041, and P = 0.032, respectively) and tumor stage (P = 0.019, P = 0.013, and P = 0.025, respectively) in the 3 sets. Moreover, multivariate analysis identified TINs and tumor node metastasis (TNM) stage as 2 independent prognostic factors for overall survival. Incorporation of TINs into well-established TNM system generated a predictive model that shows better predictive accuracy for overall survival. More importantly, patients with higher TINs were prone to overall survival benefit from postoperative adjuvant chemotherapy. These results were validated in the independent testing and validation sets. TIN in gastric cancer was identified as an independent prognostic factor, which could be incorporated into standard TNM staging system to refine risk stratification and predict for overall survival benefit from postoperative chemotherapy in patients with gastric cancer.

Prognostic value of circulating microRNAs in upper tract urinary carcinoma.

PubMed

Montalbo, Ruth; Izquierdo, Laura; Ingelmo-Torres, Mercedes; Lozano, Juan José; Capitán, David; Alcaraz, Antonio; Mengual, Lourdes

2018-03-30

The identification of upper tract urinary carcinoma (UTUC) prognostic biomarkers is urgently needed to predict tumour progression. This study aimed to identify serum microRNAs (miRNAs) that may be useful as minimally invasive predictive biomarkers of tumour progression and survival in UTUC patients. To this end, 33 UTUC patients who underwent radical nephroureterectomy at the Hospital Clinic of Barcelona were prospectively included. Expression of 800 miRNAs was evaluated in serum samples from these patients using nCounter® miRNA Expression Assays. The study was divided into an initial discovery phase (n=12) and a validation phase (n=21). Cox regression analysis was used for survival analysis. The median follow-up (range) of the series was 42 months (9-100 months). In the discovery phase, 38 differentially expressed miRNAs were identified between progressing and non-progressing UTUC patients (p<0.05). Validation of these 38 miRNAs in an independent set of UTUC patients confirmed the differential expression in 18 of them (p<0.05). Cox Regression analysis showed miR-151b and pathological stage as significant prognostic factors for tumour progression (HR=0.33, p<0.001 and HR=2.62, p=0.006, respectively) and cancer specific survival (HR=0.25, p<0.001 and HR=3.98, p=0.003, respectively). Survival curves revealed that miR-151b is able to discriminate between two groups of UTUC patients with a highly significant different probability of tumour progression (p=0.006) and cancer specific survival (p=0.034). Although the data needs to be externally validated, miRNA analysis in serum appears to be a valuable prognostic tool in UTUC patients. Particularly, differential expression of miR-151b in serum may serve as a minimally invasive prognostic tool in UTUC.

Prognostic factors in non-surgically treated sciatica: a systematic review.

PubMed

Ashworth, Julie; Konstantinou, Kika; Dunn, Kate M

2011-09-25

When present sciatica is considered an obstacle to recovery in low back pain patients, yet evidence is limited regarding prognostic factors for persistent disability in this patient group. The aim of this study is to describe and summarise the evidence regarding prognostic factors for sciatica in non-surgically treated cohorts. Understanding the prognostic factors in sciatica and their relative importance may allow the identification of patients with particular risk factors who might benefit from early or specific types of treatment in order to optimise outcome. A systematic literature search was conducted using Medline, EMBASE and CINAHL electronic databases. Prospective cohort studies describing subjects with sciatica and measuring pain, disability or recovery outcomes were included. Studies of cohorts comprised entirely of surgically treated patients were excluded and mixed surgically and conservatively treated cohorts were included only if the results were analysed separately by treatment group or if the analysis was adjusted for treatment. Seven adequate or high quality eligible studies were identified. There were conflicting but mainly negative results regarding the influence of baseline pain severity, neurological deficit, nerve root tension signs, duration of symptoms and radiological findings on outcome. A number of factors including age, gender, smoking, previous history of sciatica and heaviness of work do not appear to influence outcome. In contrast to studies of low back pain and purely surgically treated sciatica cohorts, psychological factors were rarely investigated. At present, the heterogeneity of the available studies makes it difficult to draw firm conclusions about sciatica prognosis, and highlights the need for further research for this group of patients. Large scale prospective studies of high methodological quality, using a well-defined, consistent definition of sciatica and investigating psychosocial factors alongside clinical and radiological findings are recommended to identify prognostic factors in this population.

Prognostic factors in non-surgically treated sciatica: A systematic review

PubMed Central

2011-01-01

Background When present sciatica is considered an obstacle to recovery in low back pain patients, yet evidence is limited regarding prognostic factors for persistent disability in this patient group. The aim of this study is to describe and summarise the evidence regarding prognostic factors for sciatica in non-surgically treated cohorts. Understanding the prognostic factors in sciatica and their relative importance may allow the identification of patients with particular risk factors who might benefit from early or specific types of treatment in order to optimise outcome. Methods A systematic literature search was conducted using Medline, EMBASE and CINAHL electronic databases. Prospective cohort studies describing subjects with sciatica and measuring pain, disability or recovery outcomes were included. Studies of cohorts comprised entirely of surgically treated patients were excluded and mixed surgically and conservatively treated cohorts were included only if the results were analysed separately by treatment group or if the analysis was adjusted for treatment. Results Seven adequate or high quality eligible studies were identified. There were conflicting but mainly negative results regarding the influence of baseline pain severity, neurological deficit, nerve root tension signs, duration of symptoms and radiological findings on outcome. A number of factors including age, gender, smoking, previous history of sciatica and heaviness of work do not appear to influence outcome. In contrast to studies of low back pain and purely surgically treated sciatica cohorts, psychological factors were rarely investigated. Conclusions At present, the heterogeneity of the available studies makes it difficult to draw firm conclusions about sciatica prognosis, and highlights the need for further research for this group of patients. Large scale prospective studies of high methodological quality, using a well-defined, consistent definition of sciatica and investigating psychosocial factors alongside clinical and radiological findings are recommended to identify prognostic factors in this population. PMID:21943339

Google Goes Cancer: Improving Outcome Prediction for Cancer Patients by Network-Based Ranking of Marker Genes

PubMed Central

Roy, Janine; Aust, Daniela; Knösel, Thomas; Rümmele, Petra; Jahnke, Beatrix; Hentrich, Vera; Rückert, Felix; Niedergethmann, Marco; Weichert, Wilko; Bahra, Marcus; Schlitt, Hans J.; Settmacher, Utz; Friess, Helmut; Büchler, Markus; Saeger, Hans-Detlev; Schroeder, Michael; Pilarsky, Christian; Grützmann, Robert

2012-01-01

Predicting the clinical outcome of cancer patients based on the expression of marker genes in their tumors has received increasing interest in the past decade. Accurate predictors of outcome and response to therapy could be used to personalize and thereby improve therapy. However, state of the art methods used so far often found marker genes with limited prediction accuracy, limited reproducibility, and unclear biological relevance. To address this problem, we developed a novel computational approach to identify genes prognostic for outcome that couples gene expression measurements from primary tumor samples with a network of known relationships between the genes. Our approach ranks genes according to their prognostic relevance using both expression and network information in a manner similar to Google's PageRank. We applied this method to gene expression profiles which we obtained from 30 patients with pancreatic cancer, and identified seven candidate marker genes prognostic for outcome. Compared to genes found with state of the art methods, such as Pearson correlation of gene expression with survival time, we improve the prediction accuracy by up to 7%. Accuracies were assessed using support vector machine classifiers and Monte Carlo cross-validation. We then validated the prognostic value of our seven candidate markers using immunohistochemistry on an independent set of 412 pancreatic cancer samples. Notably, signatures derived from our candidate markers were independently predictive of outcome and superior to established clinical prognostic factors such as grade, tumor size, and nodal status. As the amount of genomic data of individual tumors grows rapidly, our algorithm meets the need for powerful computational approaches that are key to exploit these data for personalized cancer therapies in clinical practice. PMID:22615549

Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer.

PubMed

Yu, Jun; Wu, William K K; Li, Xiangchun; He, Jun; Li, Xiao-Xing; Ng, Simon S M; Yu, Chang; Gao, Zhibo; Yang, Jie; Li, Miao; Wang, Qiaoxiu; Liang, Qiaoyi; Pan, Yi; Tong, Joanna H; To, Ka F; Wong, Nathalie; Zhang, Ning; Chen, Jie; Lu, Youyong; Lai, Paul B S; Chan, Francis K L; Li, Yingrui; Kung, Hsiang-Fu; Yang, Huanming; Wang, Jun; Sung, Joseph J Y

2015-04-01

Characterisation of colorectal cancer (CRC) genomes by next-generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication. To identify recurrent somatic mutations with prognostic significance in patients with CRC. Exome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurrent and pathway-related genes using targeted capture sequencing in additional 160 cases. Seven significantly mutated genes, including four reported (APC, TP53, KRAS and SMAD4) and three novel recurrently mutated genes (CDH10, FAT4 and DOCK2), exhibited high mutation prevalence (6-14% for novel cancer genes) and higher-than-expected number of non-silent mutations in our CRC cohort. For prognostication, a five-gene-signature (CDH10, COL6A3, SMAD4, TMEM132D, VCAN) was devised, in which mutation(s) in one or more of these genes was significantly associated with better overall survival independent of tumor-node-metastasis (TNM) staging. The median survival time was 80.4 months in the mutant group versus 42.4 months in the wild type group (p=0.0051). The prognostic significance of this signature was successfully verified using the data set from the Cancer Genome Atlas study. The application of next-generation sequencing has led to the identification of three novel significantly mutated genes in CRC and a mutation signature that predicts survival outcomes for stratifying patients with CRC independent of TNM staging. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Infused autograft lymphocyte-to-monocyte ratio and survival in T-cell lymphoma post-autologous peripheral blood hematopoietic stem cell transplantation.

PubMed

Porrata, Luis F; Inwards, David J; Ansell, Stephen M; Micallef, Ivana N; Johnston, Patrick B; Hogan, William J; Markovic, Svetomir N

2015-07-03

The infused autograft lymphocyte-to-monocyte ratio (A-LMR) is a prognostic factor for survival in B-cell lymphomas post-autologous peripheral hematopoietic stem cell transplantation (APHSCT). Thus, we set out to investigate if the A-LMR is also a prognostic factor for survival post-APHSCT in T-cell lymphomas. From 1998 to 2014, 109 T-cell lymphoma patients that underwent APHSCT were studied. Receiver operating characteristic (ROC) and area under the curve (AUC) were used to identify the optimal cut-off value of A-LMR for survival analysis and k-fold cross-validation model to validate the A-LMR cut-off value. Univariate and multivariate Cox proportional hazard models were used to assess the prognostic discriminator power of A-LMR. ROC and AUC identified an A-LMR ≥ 1 as the best cut-off value and was validated by k-fold cross-validation. Multivariate analysis showed A-LMR to be an independent prognostic factor for overall survival (OS) and progression-free survival (PFS). Patients with an A-LMR ≥ 1.0 experienced a superior OS and PFS versus patients with an A-LMR < 1.0 [median OS was not reached vs 17.9 months, 5-year OS rates of 87% (95% confidence interval (CI), 75-94%) vs 26% (95% CI, 13-42%), p < 0.0001; median PFS was not reached vs 11.9 months, 5-year PFS rates of 72% (95% CI, 58-83%) vs 16% (95% CI, 6-32%), p < 0.0001]. A-LMR is also a prognostic factor for clinical outcomes in patients with T-cell lymphomas undergoing APHSCT.

Prognostic factors in Acanthamoeba keratitis.

PubMed

Kaiserman, Igor; Bahar, Irit; McAllum, Penny; Srinivasan, Sathish; Elbaz, Uri; Slomovic, Allan R; Rootman, David S

2012-06-01

To assess the prognostic factors influencing visual prognosis and length of treatment after acanthamoeba keratitis (AK). Forty-two AK eyes of 41 patients treated between 1999 and 2006 were included. A diagnosis of AK was made on the basis of culture results with a corresponding clinical presentation. We calculated the prognostic effect of the various factors on final visual acuity and the length of treatment. Multivariate regression analysis was used to adjust for the simultaneous effects of the various prognostic factors. Mean follow-up was 19.7 ± 21.0 months. Sixty-four percent of cases had > 1 identified risk factor for AK, the most common risk factor being contact lens wear (92.9% of eyes). At presentation, median best spectacle corrected visual acuity (BCVA) was 20/200 (20/30 to Hand Motion [HM]) that improved after treatment to 20/50 (20/20 to Counting Fingers [CF]). Infection acquired by swimming or related to contact lenses had significantly better final BCVA (p = 0.03 and p = 0.007, respectively). Neuritis and pseudodendrites were also associated with better final BCVA (p = 0.04 and p = 0.05, respectively). Having had an epithelial defect on presentation and having been treated with topical steroid were associated with worse final best spectacle corrected visual acuity (BSCVA) (p = 0.0006 and p = 0.04). Multivariate regression analysis found a good initial visual acuity (p = 0.002), infections related to swimming (p = 0.01), the absence of an epithelial defect (p = 0.03), having been treated with chlorhexidine (p = 0.05), and not having receive steroids (p = 0.003) to significantly forecast a good final BCVA. We identified several prognostic factors that can help clinicians evaluate the expected visual damage of the AK infection and thus tailor treatment accordingly. Copyright © 2012 Canadian Ophthalmological Society. All rights reserved.

Clinical performance validation of PITX2 DNA methylation as prognostic biomarker in patients with head and neck squamous cell carcinoma.

PubMed

Sailer, Verena; Gevensleben, Heidrun; Dietrich, Joern; Goltz, Diane; Kristiansen, Glen; Bootz, Friedrich; Dietrich, Dimo

2017-01-01

Despite advances in combined modality therapy, outcomes in head and neck squamous cell cancer (HNSCC) remain dismal with five-year overall survival rates of less than 50%. Prognostic biomarkers are urgently needed to identify patients with a high risk of death after initial curative treatment. Methylation status of the paired-like homeodomain transcription factor 2 (PITX2) has recently emerged as a powerful prognostic biomarker in various cancers. In the present study, the clinical performance of PITX2 methylation was validated in a HNSCC cohort by means of an independent analytical platform (Infinium HumanMethylation450 BeadChip, Illumina, Inc.). A total of 528 HNSCC patients from The Cancer Genome Atlas (TCGA) were included in the study. Death was defined as primary endpoint. PITX2 methylation was correlated with overall survival and clinicopathological parameters. PITX2 methylation was significantly associated with sex, tumor site, p16 status, and grade. In univariate Cox proportional hazards analysis, PITX2 hypermethylation analyzed as continuous and dichotomized variable was significantly associated with prolonged overall survival of HNSCC patients (continuous: hazard ratio (HR) = 0.19 [95%CI: 0.04-0.88], p = 0.034; dichotomized: HR = 0.52 [95%CI: 0.33-0.84], p = 0.007). In multivariate Cox analysis including established clinicopathological parameters, PITX2 promoter methylation was confirmed as prognostic factor (HR = 0.28 [95%CI: 0.09-0.84], p = 0.023). Using an independent analytical platform, PITX2 methylation was validated as a prognostic biomarker in HNSCC patients, identifying patients that potentially benefit from intensified surveillance and/or administration of adjuvant/neodjuvant treatment, i.e. immunotherapy.

Development Of A Multivariate Prognostic Model For Pain And Activity Limitation In People With Low Back Disorders Receiving Physiotherapy.

PubMed

Ford, Jon J; Richards BPhysio, Matt C; Surkitt BPhysio, Luke D; Chan BPhysio, Alexander Yp; Slater, Sarah L; Taylor, Nicholas F; Hahne, Andrew J

2018-05-28

To identify predictors for back pain, leg pain and activity limitation in patients with early persistent low back disorders. Prospective inception cohort study; Setting: primary care private physiotherapy clinics in Melbourne, Australia. 300 adults aged 18-65 years with low back and/or referred leg pain of ≥6-weeks and ≤6-months duration. Not applicable. Numerical rating scales for back pain and leg pain as well as the Oswestry Disability Scale. Prognostic factors included sociodemographics, treatment related factors, subjective/physical examination, subgrouping factors and standardized questionnaires. Univariate analysis followed by generalized estimating equations were used to develop a multivariate prognostic model for back pain, leg pain and activity limitation. Fifty-eight prognostic factors progressed to the multivariate stage where 15 showed significant (p<0.05) associations with at least one of the three outcomes. There were five indicators of positive outcome (two types of low back disorder subgroups, paresthesia below waist, walking as an easing factor and low transversus abdominis tone) and 10 indicators of negative outcome (both parents born overseas, deep leg symptoms, longer sick leave duration, high multifidus tone, clinically determined inflammation, higher back and leg pain severity, lower lifting capacity, lower work capacity and higher pain drawing percentage coverage). The preliminary model identifying predictors of low back disorders explained up to 37% of the variance in outcome. This study evaluated a comprehensive range of prognostic factors reflective of both the biomedical and psychosocial domains of low back disorders. The preliminary multivariate model requires further validation before being considered for clinical use. Copyright © 2018. Published by Elsevier Inc.

CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900

PubMed Central

Gönen, Mithat; Sun, Zhuoxin; Figueroa, Maria E.; Patel, Jay P.; Abdel-Wahab, Omar; Racevskis, Janis; Ketterling, Rhett P.; Fernandez, Hugo; Rowe, Jacob M.; Tallman, Martin S.; Melnick, Ari; Levine, Ross L.

2012-01-01

We determined the prognostic relevance of CD25 (IL-2 receptor-α) expression in 657 patients (≤ 60 years) with de novo acute myeloid leukemia (AML) treated in the Eastern Cooperative Oncology Group trial, E1900. We identified CD25POS myeloblasts in 87 patients (13%), of whom 92% had intermediate-risk cytogenetics. CD25 expression correlated with expression of stem cell antigen CD123. In multivariate analysis, controlled for prognostic baseline characteristics and daunorubicin dose, CD25POS patients had inferior complete remission rates (P = .0005) and overall survival (P < .0001) compared with CD25NEG cases. In a subset of 396 patients, we integrated CD25 expression with somatic mutation status to determine whether CD25 impacted outcome independent of prognostic mutations. CD25 was positively correlated with internal tandem duplications in FLT3 (FLT3-ITD), DNMT3A, and NPM1 mutations. The adverse prognostic impact of FLT3-ITDPOS AML was restricted to CD25POS patients. CD25 expression improved AML prognostication independent of integrated, cytogenetic and mutational data, such that it reallocated 11% of patients with intermediate-risk disease to the unfavorable-risk group. Gene expression analysis revealed that CD25POS status correlated with the expression of previously reported leukemia stem cell signatures. We conclude that CD25POS status provides prognostic relevance in AML independent of known biomarkers and is correlated with stem cell gene-expression signatures associated with adverse outcome in AML. PMID:22855599

Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta-analysis

PubMed Central

Shao, Yingjie; Xu, Bin; Chen, Lujun; Zhou, Qi; Hu, Wenwei; Zhang, Dachuan; Wu, Changping; Tao, Min; Zhu, Yibei; Jiang, Jingting

2017-01-01

Background In patients with gastric cancer, the prognostic value of tumor-infiltrating lymphocytes (TILs) is still controversial. A meta-analysis was performed to evaluate the prognostic value of TILs in gastric cancer. Materials and methods We identify studies from PubMed, Embase and the Cochrane Library to assess the prognostic effect of TILs in patients with gastric cancer. Fixed-effects models or random-effects models were used estimate the pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS), which depend on the heterogeneity. Results A total of 31 observational studies including 4,185 patients were enrolled. For TILs subsets, the amount of CD8+, FOXP3+, CD3+, CD57+, CD20+, CD45RO+, Granzyme B+ and T-bet+ lymphocytes was significantly associated with improved survival (P < 0.05); moreover, the amount of CD3+ TILs in intra-tumoral compartment (IT) was the most significant prognostic marker (pooled HR = 0.52; 95% CI = 0.43–0.63; P < 0.001). However, CD4+ TILs was not statistically associated with patients’ survival. FOXP3+ TILs showed bidirectional prognostic roles which had positive effect in IT (pooled HR = 1.57; 95% CI = 1.04–2.37; P = 0.033) and negative effect in extra-tumoral compartment (ET) (pooled HR = 0.76; 95% CI = 0.60–0.96; P = 0.022). Conclusions This meta-analysis suggests that some TIL subsets could serve as prognostic biomarkers in gastric cancer. High-quality randomized controlled trials are needed to decide if these TILs could serve as targets for immunotherapy in gastric cancer. PMID:28915679

Validation of cytogenetic risk groups according to International Prognostic Scoring Systems by peripheral blood CD34+FISH: results from a German diagnostic study in comparison with an international control group

PubMed Central

Braulke, Friederike; Platzbecker, Uwe; Müller-Thomas, Catharina; Götze, Katharina; Germing, Ulrich; Brümmendorf, Tim H.; Nolte, Florian; Hofmann, Wolf-Karsten; Giagounidis, Aristoteles A. N.; Lübbert, Michael; Greenberg, Peter L.; Bennett, John M.; Solé, Francesc; Mallo, Mar; Slovak, Marilyn L.; Ohyashiki, Kazuma; Le Beau, Michelle M.; Tüchler, Heinz; Pfeilstöcker, Michael; Nösslinger, Thomas; Hildebrandt, Barbara; Shirneshan, Katayoon; Aul, Carlo; Stauder, Reinhard; Sperr, Wolfgang R.; Valent, Peter; Fonatsch, Christa; Trümper, Lorenz; Haase, Detlef; Schanz, Julie

2015-01-01

International Prognostic Scoring Systems are used to determine the individual risk profile of myelodysplastic syndrome patients. For the assessment of International Prognostic Scoring Systems, an adequate chromosome banding analysis of the bone marrow is essential. Cytogenetic information is not available for a substantial number of patients (5%–20%) with dry marrow or an insufficient number of metaphase cells. For these patients, a valid risk classification is impossible. In the study presented here, the International Prognostic Scoring Systems were validated based on fluorescence in situ hybridization analyses using extended probe panels applied to cluster of differentiation 34 positive (CD34+) peripheral blood cells of 328 MDS patients of our prospective multicenter German diagnostic study and compared to chromosome banding results of 2902 previously published patients with myelodysplastic syndromes. For cytogenetic risk classification by fluorescence in situ hybridization analyses of CD34+ peripheral blood cells, the groups differed significantly for overall and leukemia-free survival by uni- and multivariate analyses without discrepancies between treated and untreated patients. Including cytogenetic data of fluorescence in situ hybridization analyses of peripheral CD34+ blood cells (instead of bone marrow banding analysis) into the complete International Prognostic Scoring System assessment, the prognostic risk groups separated significantly for overall and leukemia-free survival. Our data show that a reliable stratification to the risk groups of the International Prognostic Scoring Systems is possible from peripheral blood in patients with missing chromosome banding analysis by using a comprehensive probe panel (clinicaltrials.gov identifier:01355913). PMID:25344522

Prognostic score to predict mortality during TB treatment in TB/HIV co-infected patients.

PubMed

Nguyen, Duc T; Jenkins, Helen E; Graviss, Edward A

2018-01-01

Estimating mortality risk during TB treatment in HIV co-infected patients is challenging for health professionals, especially in a low TB prevalence population, due to the lack of a standardized prognostic system. The current study aimed to develop and validate a simple mortality prognostic scoring system for TB/HIV co-infected patients. Using data from the CDC's Tuberculosis Genotyping Information Management System of TB patients in Texas reported from 01/2010 through 12/2016, age ≥15 years, HIV(+), and outcome being "completed" or "died", we developed and internally validated a mortality prognostic score using multiple logistic regression. Model discrimination was determined by the area under the receiver operating characteristic (ROC) curve (AUC). The model's good calibration was determined by a non-significant Hosmer-Lemeshow's goodness of fit test. Among the 450 patients included in the analysis, 57 (12.7%) died during TB treatment. The final prognostic score used six characteristics (age, residence in long-term care facility, meningeal TB, chest x-ray, culture positive, and culture not converted/unknown), which are routinely collected by TB programs. Prognostic scores were categorized into three groups that predicted mortality: low-risk (<20 points), medium-risk (20-25 points) and high-risk (>25 points). The model had good discrimination and calibration (AUC = 0.82; 0.80 in bootstrap validation), and a non-significant Hosmer-Lemeshow test p = 0.71. Our simple validated mortality prognostic scoring system can be a practical tool for health professionals in identifying TB/HIV co-infected patients with high mortality risk.

Expression profiling of nuclear receptors in breast cancer identifies TLX as a mediator of growth and invasion in triple-negative breast cancer

PubMed Central

Remenyi, Judit; Banerji, Christopher R.S.; Lai, Chun-Fui; Periyasamy, Manikandan; Lombardo, Ylenia; Busonero, Claudia; Ottaviani, Silvia; Passey, Alun; Quinlan, Philip R.; Purdie, Colin A.; Jordan, Lee B.; Thompson, Alastair M.; Finn, Richard S.; Rueda, Oscar M.; Caldas, Carlos; Gil, Jesus; Coombes, R. Charles; Fuller-Pace, Frances V.; Teschendorff, Andrew E.; Buluwela, Laki; Ali, Simak

2015-01-01

The Nuclear Receptor (NR) superfamily of transcription factors comprises 48 members, several of which have been implicated in breast cancer. Most important is estrogen receptor-α (ERα), which is a key therapeutic target. ERα action is facilitated by co-operativity with other NR and there is evidence that ERα function may be recapitulated by other NRs in ERα-negative breast cancer. In order to examine the inter-relationships between nuclear receptors, and to obtain evidence for previously unsuspected roles for any NRs, we undertook quantitative RT-PCR and bioinformatics analysis to examine their expression in breast cancer. While most NRs were expressed, bioinformatic analyses differentiated tumours into distinct prognostic groups that were validated by analyzing public microarray data sets. Although ERα and progesterone receptor were dominant in distinguishing prognostic groups, other NR strengthened these groups. Clustering analysis identified several family members with potential importance in breast cancer. Specifically, RORγ is identified as being co-expressed with ERα, whilst several NRs are preferentially expressed in ERα-negative disease, with TLX expression being prognostic in this subtype. Functional studies demonstrated the importance of TLX in regulating growth and invasion in ERα-negative breast cancer cells. PMID:26280373

[Prognostic and predictive molecular markers for urologic cancers].

PubMed

Hartmann, A; Schlomm, T; Bertz, S; Heinzelmann, J; Hölters, S; Simon, R; Stoehr, R; Junker, K

2014-04-01

Molecular prognostic factors and genetic alterations as predictive markers for cancer-specific targeted therapies are used today in the clinic for many malignancies. In recent years, many molecular markers for urogenital cancers have also been identified. However, these markers are not clinically used yet. In prostate cancer, novel next-generation sequencing methods revealed a detailed picture of the molecular changes. There is growing evidence that a combination of classical histopathological and validated molecular markers could lead to a more precise estimation of prognosis, thus, resulting in an increasing number of patients with active surveillance as a possible treatment option. In patients with urothelial carcinoma, histopathological factors but also the proliferation of the tumor, mutations in oncogenes leading to an increasing proliferation rate and changes in genes responsible for invasion and metastasis are important. In addition, gene expression profiles which could distinguish aggressive tumors with high risk of metastasis from nonmetastasizing tumors have been recently identified. In the future, this could potentially allow better selection of patients needing systemic perioperative treatment. In renal cell carcinoma, many molecular markers that are associated with metastasis and survival have been identified. Some of these markers were also validated as independent prognostic markers. Selection of patients with primarily organ-confined tumors and increased risk of metastasis for adjuvant systemic therapy could be clinically relevant in the future.

Significant Prognostic Factors for Completely Resected pN2 Non-small Cell Lung Cancer without Neoadjuvant Therapy

PubMed Central

Nakao, Masayuki; Mun, Mingyon; Nakagawa, Ken; Nishio, Makoto; Ishikawa, Yuichi; Okumura, Sakae

2015-01-01

Purpose: To identify prognostic factors for pathologic N2 (pN2) non-small cell lung cancer (NSCLC) treated by surgical resection. Methods: Between 1990 and 2009, 287 patients with pN2 NSCLC underwent curative resection at the Cancer Institute Hospital without preoperative treatment. Results: The 5-year overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) rates were 46%, 55% and 24%, respectively. The median follow-up time was 80 months. Multivariate analysis identified four independent predictors for poor OS: multiple-zone mediastinal lymph node metastasis (hazard ratio [HR], 1.616; p = 0.003); ipsilateral intrapulmonary metastasis (HR, 1.042; p = 0.002); tumor size >30 mm (HR, 1.013; p = 0.002); and clinical stage N1 or N2 (HR, 1.051; p = 0.030). Multivariate analysis identified three independent predictors for poor RFS: multiple-zone mediastinal lymph node metastasis (HR, 1.457; p = 0.011); ipsilateral intrapulmonary metastasis (HR, 1.040; p = 0.002); and tumor size >30 mm (HR, 1.008; p = 0.032). Conclusion: Multiple-zone mediastinal lymph node metastasis, ipsilateral intrapulmonary metastasis, and tumor size >30 mm were common independent prognostic factors of OS, CSS, and RFS in pN2 NSCLC. PMID:25740454

Ability of the VITEK 2 Advanced Expert System To Identify β-Lactam Phenotypes in Isolates of Enterobacteriaceae and Pseudomonas aeruginosa

PubMed Central

Sanders, Christine C.; Peyret, Michel; Moland, Ellen Smith; Shubert, Carole; Thomson, Kenneth S.; Boeufgras, Jean-Marc; Sanders, W. Eugene

2000-01-01

The Advanced Expert System (AES) was used in conjunction with the VITEK 2 automated antimicrobial susceptibility test system to ascertain the β-lactam phenotypes of 196 isolates of the family Enterobacteriaceae and the species Pseudomonas aeruginosa. These isolates represented a panel of strains that had been collected from laboratories worldwide and whose β-lactam phenotypes had been characterized by biochemical and molecular techniques. The antimicrobial susceptibility of each isolate was determined with the VITEK 2 instrument, and the results were analyzed with the AES to ascertain the β-lactam phenotype. The results were then compared to the β-lactam resistance mechanism determined by biochemical and molecular techniques. Overall, the AES was able to ascertain a β-lactam phenotype for 183 of the 196 (93.4%) isolates tested. For 111 of these 183 (60.7%) isolates, the correct β-lactam phenotype was identified definitively in a single choice by the AES, while for an additional 46 isolates (25.1%), the AES identified the correct β-lactam phenotype provisionally within two or more choices. For the remaining 26 isolates (14.2%), the β-lactam phenotype identified by the AES was incorrect. However, for a number of these isolates, the error was due to remediable problems. These results suggest that the AES is capable of accurate identification of the β-lactam phenotypes of gram-negative isolates and that certain modifications can improve its performance even further. PMID:10655347

Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer.

PubMed

Chen, Jie; Li, Yan; Zheng, Qiupeng; Bao, Chunyang; He, Jian; Chen, Bin; Lyu, Dongbin; Zheng, Biqiang; Xu, Yu; Long, Ziwen; Zhou, Ye; Zhu, Huiyan; Wang, Yanong; He, Xianghuo; Shi, Yingqiang; Huang, Shenglin

2017-03-01

Circular RNAs (circRNAs) comprise a novel class of widespread non-coding RNAs that may regulate gene expression in eukaryotes. However, the characterization and function of circRNAs in human cancer remain elusive. Here we identified at least 5500 distinct circRNA candidates and a series of circRNAs that are differentially expressed in gastric cancer (GC) tissues compared with matched normal tissues. We further characterized one circRNA derived from the PVT1 gene and termed it as circPVT1. The expression of circPVT1 is often upregulated in GC tissues due to the amplification of its genomic locus. circPVT1 may promote cell proliferation by acting as a sponge for members of the miR-125 family. The level of circPVT1 was observed as an independent prognostic marker for overall survival and disease-free survival of patients with GC. Our findings suggest that circPVT1 is a novel proliferative factor and prognostic marker in GC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Integrated CLL Scoring System, a New and Simple Index to Predict Time to Treatment and Overall Survival in Patients With Chronic Lymphocytic Leukemia.

PubMed

Visentin, Andrea; Facco, Monica; Frezzato, Federica; Castelli, Monica; Trimarco, Valentina; Martini, Veronica; Gattazzo, Cristina; Severin, Filippo; Chiodin, Giorgia; Martines, Annalisa; Bonaldi, Laura; Gianesello, Ilaria; Pagnin, Elisa; Boscaro, Elisa; Piazza, Francesco; Zambello, Renato; Semenzato, Gianpietro; Trentin, Livio

2015-10-01

Several prognostic factors have been identified to predict the outcome of patients with chronic lymphocytic leukemia (CLL), but only a few studies analyzed more markers together. Taking advantage of a population of 608 patients, we identified the strongest prognostic markers of survival and, subsequently, in a cohort of 212 patients we integrated data of cytogenetic lesions, IGHV mutational status, and CD38 expression in a new and easy scoring system we called the integrated CLL scoring system (ICSS). ICSS defines 3 groups of risk: (1) low risk (patients with 13q(-) or normal fluorescence in-situ hybridization analysis results, mutated IGHV, and CD38) (2) high risk (all 11q(-) or 17p(-) patients and/or all unmutated IGHV and CD38(+) patients); and (3) intermediate risk (all remaining patients). Using only these 3 already available prognostic factors, we were able to properly redefine patients and better predict the clinical course of the disease. ICSS could become a useful tool for CLL patients' management. Copyright © 2015 Elsevier Inc. All rights reserved.

Identification of new candidate therapeutic target genes in head and neck squamous cell carcinomas

PubMed Central

Klijanienko, Jerzy; Vacher, Sophie; Ouafi, Lamia; Chemlali, Walid; Caly, Martial; Sastre-Garau, Xavier; Lappartient, Emmanuelle; Mariani, Odette; Rodriguez, José; Jouffroy, Thomas; Girod, Angélique; Calugaru, Valentin; Hoffmann, Caroline; Lidereau, Rosette; Berger, Frédérique; Kamal, Maud; Bieche, Ivan; Le Tourneau, Christophe

2016-01-01

Background We aimed at identifying druggable molecular alterations at the RNA level from untreated HNSCC patients, and assessing their prognostic significance. Methods We retrieved 96 HNSCC patients who underwent primary surgery. Real-time quantitative RT-PCR was used to analyze a panel of 42 genes coding for major druggable proteins. Univariate and multivariate analyses were performed to assess the prognostic significance of overexpressed genes. Results Median age was 56 years [35–78]. Most of patients were men (80%) with a history of alcohol (70.4%) and/or tobacco consumption (72.5%). Twelve patients (12%) were HPV-positive. Most significantly overexpressed genes involved cell cycle regulation (CCND1 [27%], CDK6 [21%]), tyrosine kinase receptors (MET [18%], EGFR [14%]), angiogenesis (PGF [301%], VEGFA [14%]), and immune system (PDL1/CD274 [28%]). PIK3CA expression was an independent prognostic marker, associated with shorter disease-free survival. Conclusions We identified druggable overexpressed genes associated with a poor outcome that might be of interest for personalizing treatment of HNSCC patients. PMID:27329726

An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma based on mRNA, microRNA and DNA Methylation Biomarkers

PubMed Central

Robles, Ana I.; Arai, Eri; Mathé, Ewy A.; Okayama, Hirokazu; Schetter, Aaron J.; Brown, Derek; Petersen, David; Bowman, Elise D.; Noro, Rintaro; Welsh, Judith A.; Edelman, Daniel C.; Stevenson, Holly S.; Wang, Yonghong; Tsuchiya, Naoto; Kohno, Takashi; Skaug, Vidar; Mollerup, Steen; Haugen, Aage; Meltzer, Paul S.; Yokota, Jun; Kanai, Yae

2015-01-01

Introduction Up to 30% Stage I lung cancer patients suffer recurrence within 5 years of curative surgery. We sought to improve existing protein-coding gene and microRNA expression prognostic classifiers by incorporating epigenetic biomarkers. Methods Genome-wide screening of DNA methylation and pyrosequencing analysis of HOXA9 promoter methylation were performed in two independently collected cohorts of Stage I lung adenocarcinoma. The prognostic value of HOXA9 promoter methylation alone and in combination with mRNA and miRNA biomarkers was assessed by Cox regression and Kaplan-Meier survival analysis in both cohorts. Results Promoters of genes marked by Polycomb in Embryonic Stem Cells were methylated de novo in tumors and identified patients with poor prognosis. The HOXA9 locus was methylated de novo in Stage I tumors (P < 0.0005). High HOXA9 promoter methylation was associated with worse cancer-specific survival (Hazard Ratio [HR], 2.6; P = 0.02) and recurrence-free survival (HR, 3.0; P = 0.01), and identified high-risk patients in stratified analysis of Stage IA and IB. Four protein-coding gene (XPO1, BRCA1, HIF1α, DLC1), miR-21 expression and HOXA9 promoter methylation were each independently associated with outcome (HR, 2.8; P = 0.002; HR, 2.3; P = 0.01; and HR, 2.4; P = 0.005, respectively), and, when combined, identified high-risk, therapy naïve, Stage I patients (HR, 10.2; P = 3x10−5). All associations were confirmed in two independently collected cohorts. Conclusion A prognostic classifier comprising three types of genomic and epigenomic data may help guide the postoperative management of Stage I lung cancer patients at high risk of recurrence. PMID:26134223

Comparison of the Prognostic Utility of the Diverse Molecular Data among lncRNA, DNA Methylation, microRNA, and mRNA across Five Human Cancers

PubMed Central

Xu, Li; Fengji, Liang; Changning, Liu; Liangcai, Zhang; Yinghui, Li; Yu, Li; Shanguang, Chen; Jianghui, Xiong

2015-01-01

Introduction Advances in high-throughput technologies have generated diverse informative molecular markers for cancer outcome prediction. Long non-coding RNA (lncRNA) and DNA methylation as new classes of promising markers are emerging as key molecules in human cancers; however, the prognostic utility of such diverse molecular data remains to be explored. Materials and Methods We proposed a computational pipeline (IDFO) to predict patient survival by identifying prognosis-related biomarkers using multi-type molecular data (mRNA, microRNA, DNA methylation, and lncRNA) from 3198 samples of five cancer types. We assessed the predictive performance of both single molecular data and integrated multi-type molecular data in patient survival stratification, and compared their relative importance in each type of cancer, respectively. Survival analysis using multivariate Cox regression was performed to investigate the impact of the IDFO-identified markers and traditional variables on clinical outcome. Results Using the IDFO approach, we obtained good predictive performance of the molecular datasets (bootstrap accuracy: 0.71–0.97) in five cancer types. Impressively, lncRNA was identified as the best prognostic predictor in the validated cohorts of four cancer types, followed by DNA methylation, mRNA, and then microRNA. We found the incorporating of multi-type molecular data showed similar predictive power to single-type molecular data, but with the exception of the lncRNA + DNA methylation combinations in two cancers. Survival analysis of proportional hazard models confirmed a high robustness for lncRNA and DNA methylation as prognosis factors independent of traditional clinical variables. Conclusion Our study provides insight into systematically understanding the prognostic performance of diverse molecular data in both single and aggregate patterns, which may have specific reference to subsequent related studies. PMID:26606135

Genes with a spike expression are clustered in chromosome (sub)bands and spike (sub)bands have a powerful prognostic value in patients with multiple myeloma

PubMed Central

Kassambara, Alboukadel; Hose, Dirk; Moreaux, Jérôme; Walker, Brian A.; Protopopov, Alexei; Reme, Thierry; Pellestor, Franck; Pantesco, Véronique; Jauch, Anna; Morgan, Gareth; Goldschmidt, Hartmut; Klein, Bernard

2012-01-01

Background Genetic abnormalities are common in patients with multiple myeloma, and may deregulate gene products involved in tumor survival, proliferation, metabolism and drug resistance. In particular, translocations may result in a high expression of targeted genes (termed spike expression) in tumor cells. We identified spike genes in multiple myeloma cells of patients with newly-diagnosed myeloma and investigated their prognostic value. Design and Methods Genes with a spike expression in multiple myeloma cells were picked up using box plot probe set signal distribution and two selection filters. Results In a cohort of 206 newly diagnosed patients with multiple myeloma, 2587 genes/expressed sequence tags with a spike expression were identified. Some spike genes were associated with some transcription factors such as MAF or MMSET and with known recurrent translocations as expected. Spike genes were not associated with increased DNA copy number and for a majority of them, involved unknown mechanisms. Of spiked genes, 36.7% clustered significantly in 149 out of 862 documented chromosome (sub)bands, of which 53 had prognostic value (35 bad, 18 good). Their prognostic value was summarized with a spike band score that delineated 23.8% of patients with a poor median overall survival (27.4 months versus not reached, P<0.001) using the training cohort of 206 patients. The spike band score was independent of other gene expression profiling-based risk scores, t(4;14), or del17p in an independent validation cohort of 345 patients. Conclusions We present a new approach to identify spike genes and their relationship to patients’ survival. PMID:22102711

An eleven gene molecular signature for extra-capsular spread in oral squamous cell carcinoma serves as a prognosticator of outcome in patients without nodal metastases.

PubMed

Wang, Weining; Lim, Weng Khong; Leong, Hui Sun; Chong, Fui Teen; Lim, Tony K H; Tan, Daniel S W; Teh, Bin Tean; Iyer, N Gopalakrishna

2015-04-01

Extracapsular spread (ECS) is an important prognostic factor for oral squamous cell carcinoma (OSCC) and is used to guide management. In this study, we aimed to identify an expression profile signature for ECS in node-positive OSCC using data derived from two different sources: a cohort of OSCC patients from our institution (National Cancer Centre Singapore) and The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) cohort. We also sought to determine if this signature could serve as a prognostic factor in node negative cancers. Patients with a histological diagnosis of OSCC were identified from an institutional database and fresh tumor samples were retrieved. RNA was extracted and gene expression profiling was performed using the Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray platform. RNA sequence data and corresponding clinical data for the TCGA HNSCC cohort were downloaded from the TCGA Data Portal. All data analyses were conducted using R package and SPSS. We identified an 11 gene signature (GGH, MTFR1, CDKN3, PSRC1, SMIM3, CA9, IRX4, CPA3, ZSCAN16, CBX7 and ZFP3) which was robust in segregating tumors by ECS status. In node negative patients, patients harboring this ECS signature had a significantly worse overall survival (p=0.04). An eleven gene signature for ECS was derived. Our results also suggest that this signature is prognostic in a separate subset of patients with no nodal metastasis Further validation of this signature on other datasets and immunohistochemical studies are required to establish utility of this signature in stratifying early stage OSCC patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

Prognostic Factors for Neurologic Outcome in Patients with Carotid Artery Stenting

PubMed Central

Hung, Chi-Sheng; Lin, Mao-Shin; Chen, Ying-Hsien; Huang, Ching-Chang; Li, Hung-Yuan; Kao, Hsien-Li

2016-01-01

Background Carotid artery stenting (CAS) is a valid treatment for patients with carotid artery stenosis. The long-term outcome and prognostic factors in Asian population after CAS are not clear. This study aimed to identify the prognostic factors among Asian patients who have undergone CAS. Methods We retrospectively analyzed 246 patients with CAS. Annual carotid duplex ultrasound was used to identify restenosis. Peri-procedural complications, restenosis, neurologic outcomes, and mortality were recorded. Cox regression analyses were used to identify prognostic factors. Results The mean follow-up time was 49.2 months. Procedural success was achieved in 237 patients (98.3%), and protection devices were used in 208 patients (84.5%). Within 30 days of CAS, 13 (4.3% per procedure) peri-procedural complications occurred. During the follow-up period, 24 (9.7%) patients developed restenosis, and 37 (15.0%) developed ischemic strokes. In a multiple logistic regression analysis, head and neck radiotherapy [hazard ratio (HR) = 9.9, 95% confidence interval (CI), 3.38-29.1, p < .001], stent diameter (HR = 0.72, 95% CI, 0.58-0.89, p = .003), and predilatation (HR = 3.08 95% CI, 1.21-7.81, p = .018) were independent predictors for restenosis. In Cox regression analysis, hypercholesterolemia (HR = 0.25, 95% CI, 0.07-0.94, p = .04), head and neck radiotherapy (HR = 6.2, 95% CI, 1.8-21.3, p = .004), and restenosis (HR = 3.6, 95% CI, 1.1-11.18, p = .04) were predictors for recurrent ipsilateral ischemic stroke. Conclusions CAS provides reliable long-term results in Asian patients with carotid stenosis. Restenosis is associated with an increased rate of recurrent stroke and should be monitored carefully following CAS. PMID:27122951

Clinical and histopathological factors associated with Ki-67 expression in breast cancer patients

PubMed Central

ALCO, GUL; BOZDOGAN, ATILLA; SELAMOGLU, DERYA; PILANCI, KEZBAN NUR; TUZLALI, SITKI; ORDU, CETIN; IGDEM, SEFIK; OKKAN, SAIT; DINCER, MAKTAV; DEMIR, GOKHAN; OZMEN, VAHIT

2015-01-01

The aim of the present study was to identify the optimal Ki-67 cut-off value in breast cancer (BC) patients, and investigate the association of Ki-67 expression levels with other prognostic factors. Firstly, a retrospective search was performed to identify patients with stage I–III BC (n=462). A range of Ki-67 index values were then assigned to five groups (<10, 10–14, 15–19, 20–24 and ≥25%). The correlation between the Ki-67 index and other prognostic factors [age, tumor type, histological and nuclear grade, tumor size, multifocality, an in situ component, lymphovascular invasion (LVI), estrogen and progesterone receptor (ER/PR) expression, human epidermal growth factor receptor (HER-2) status, axillary involvement and tumor stage] were investigated in each group. The median Ki-67 value was revealed to be 20% (range, 1–95%). A young age (≤40 years old), tumor type, size and grade, LVI, ER/PR negativity and HER-2 positivity were revealed to be associated with the Ki-67 level. Furthermore, Ki-67 was demonstrated to be negatively correlated with ER/PR expression (P<0.001), but positively correlated with tumor size (P<0.001). The multivariate analysis revealed that a Ki-67 value of ≥15% was associated with the largest number of poor prognostic factors (P=0.036). In addition, a Ki-67 value of ≥15% was identified to be statistically significant in association with certain luminal subtypes. The rate of disease-free survival was higher in patients with luminal A subtype BC (P=0.036). Following the correlation analysis for the Ki-67 index and the other prognostic factors, a Ki-67 value of ≥15% was revealed to be the optimal cut-off level for BC patients. PMID:25663855

Prognostic value of Ki-67 index in adult medulloblastoma after accounting for molecular subgroup: a retrospective clinical and molecular analysis.

PubMed

Zhao, Fu; Zhang, Jing; Li, Peng; Zhou, Qiangyi; Zhang, Shun; Zhao, Chi; Wang, Bo; Yang, Zhijun; Li, Chunde; Liu, Pinan

2018-04-23

Medulloblastoma (MB) is a rare primary brain tumor in adults. We previously evaluated that combining both clinical and molecular classification could improve current risk stratification for adult MB. In this study, we aimed to identify the prognostic value of Ki-67 index in adult MB. Ki-67 index of 51 primary adult MBs was reassessed using a computer-based image analysis (Image-Pro Plus). All patients were followed up ranging from 12 months up to 15 years. Gene expression profiling and immunochemistry were used to establish the molecular subgroups in adult MB. Combined risk stratification models were designed based on clinical characteristics, molecular classification and Ki-67 index, and identified by multivariable Cox proportional hazards analysis. In our cohort, the mean Ki-67 value was 30.0 ± 11.3% (range 6.56-63.55%). The average Ki-67 value was significantly higher in LC/AMB than in CMB and DNMB (P = .001). Among three molecular subgroups, Group 4-tumors had the highest average Ki-67 value compared with WNT- and SHH-tumors (P = .004). Patients with Ki-67 index large than 30% displayed poorer overall survival (OS) and progression free survival (PFS) than those with Ki-67 less than 30% (OS: P = .001; PFS: P = .006). Ki-67 index (i.e. > 30%, < 30%) was identified as an independent significant prognostic factor (OS: P = .017; PFS: P = .024) by using multivariate Cox proportional hazards model. In conclusion, Ki-67 index can be considered as a valuable independent prognostic biomarker for adult patients with MB.

Comparison of Comorbidity Collection Methods

PubMed Central

Kallogjeri, Dorina; Gaynor, Sheila M; Piccirillo, Marilyn L; Jean, Raymond A; Spitznagel, Edward L; Piccirillo, Jay F

2014-01-01

Background Multiple valid comorbidity indices exist to quantify the presence and role of comorbidities in cancer patient survival. Our goal was to compare chart-based Adult Comorbidity Evaluation-27 index (ACE-27), and claims-based Charlson Comorbidity Index (CCI) methods of identifying comorbid ailments, and their prognostic ability. Study Design Prospective cohort study of 6138 newly-diagnosed cancer patients at 12 different institutions. Participating registrars were trained to collect comorbidities from the abstracted chart using the ACE-27 method. ACE-27 assessment was compared with comorbidities captured through hospital discharge face-sheets using ICD-coding. The prognostic accomplishments of each comorbidity method was examined using follow-up data assessed at 24 months after data abstraction. Results Distribution of the ACE-27 scores was: “None” for 1453 (24%) of the patients; “Mild” for 2388 (39%); “Moderate” for 1344 (22%) and “Severe” for 950 (15%) of the patients. Deyo’s adaption of the Charlson Comorbidity Index (CCI) identified 4265 (69%) patients with a CCI score of 0, and the remaining 31% had CCI scores of 1 (n=1341, 22%), 2 (n=365, 6%), or 3 or more (n=167, 3%). Of the 4265 patients with a CCI score of 0, 394 (9%) were coded with severe comorbidities based on ACE-27 method. A higher comorbidity score was significantly associated with higher risk of death for both comorbidity indices. The multivariable Cox model including both comorbidity indices had the best performance (Nagelkerke’s R-square=0.37) and the best discrimination (c-index=0.827). Conclusion The number, type, and overall severity of comorbid ailments identified by chart- and claims-based approaches in newly-diagnosed cancer patients were notably different. Both indices were prognostically significant and able to provide unique prognostic information. PMID:24933715

Prognostic markers and tumour growth kinetics in melanoma patients progressing on vemurafenib.

PubMed

Seifert, Heike; Fisher, Rosalie; Martin-Liberal, Juan; Edmonds, Kim; Hughes, Peta; Khabra, Komel; Gore, Martin; Larkin, James

2016-04-01

The BRAF inhibitor vemurafenib is an effective drug in patients with BRAF mutant metastatic melanoma, but resistance occurs after a median of 6 months. The anti-CTLA4-antibody, ipilimumab, is a standard first-line and second-line treatment option in Europe, with a median time to response of 2-3 months, but some patients show rapid clinical deterioration before that. The aim of this analysis was to identify prognostic markers for survival after failure of vemurafenib treatment to identify patients who have a sufficient life expectancy to respond to new immunotherapy treatments. We retrospectively analysed 101 consecutive unselected patients treated with vemurafenib for metastatic melanoma at a single institution. The association between clinical parameters and death within 3 months after cessation of vemurafenib (n=69) was assessed by binary logistic and Cox regression. Of the patients, 45% died within 3 months of progression on vemurafenib. Elevated baseline serum lactate dehydrogenase, absence of normalization of serum lactate dehydrogenase on vemurafenib therapy, performance status of at least 2 at progression and time from primary tumour to metastatic disease less than 5 years were identified as poor prognostic markers. In an exploratory tumour growth kinetics analysis (n=16), we found that following cessation of vemurafenib, approximately a third each showed a stable, decelerated or accelerated rate of tumour growth. Patients with these poor prognostic markers are unlikely to have sufficient life expectancy to complete ipilimumab treatment after failure with vemurafenib. Consideration needs to be given to the elective use of immunotherapy before patients become resistant to vemurafenib. This requires prospective randomized evaluation. Our tumour growth kinetics analysis requires confirmation; however, it may suggest that intermittent vemurafenib treatment should be investigated in clinical trials.

Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers

PubMed Central

Weiduschat, Nora; Kaufmann, Petra; Mao, Xiangling; Engelstad, Kristin Marie; Hinton, Veronica; DiMauro, Salvatore; De Vivo, Darryl

2014-01-01

Objective: To establish cerebral metabolic features associated with the A3243G mitochondrial DNA mutation with proton magnetic resonance spectroscopic imaging (1H MRSI) and to assess their potential as prognostic biomarkers. Methods: In this prospective cohort study, we investigated 135 clinically heterogeneous A3243G mutation carriers and 30 healthy volunteers (HVs) with 1H MRSI. Mutation carriers included 45 patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); 11 participants who would develop the MELAS syndrome during follow-up (converters); and 79 participants who would not develop the MELAS syndrome during follow-up (nonconverters). The groups were compared with respect to MRSI metabolic indices of 1) anaerobic energy metabolism (lactate), 2) neuronal integrity (N-acetyl-l-aspartate [NAA]), 3) mitochondrial function (NAA; lactate), 4) cell energetics (total creatine), and 5) membrane biosynthesis and turnover (total choline [tCho]). Results: Consistent with prior studies, the patients with MELAS had higher lactate (p < 0.001) and lower NAA levels (p = 0.01) than HVs. Unexpectedly, converters showed higher NAA (p = 0.042), tCho (p = 0.004), and total creatine (p = 0.002), in addition to higher lactate levels (p = 0.032), compared with HVs. Compared with nonconverters, converters had higher tCho (p = 0.015). Clinically, converters and nonconverters did not differ at baseline. Lactate and tCho levels were reliable biomarkers for predicting the risk of individual mutation carriers to develop the MELAS phenotype. Conclusions: 1H MRSI assessment of cerebral metabolism in A3243G mutation carriers shows promise in identifying disease biomarkers as well as individuals at risk of developing the MELAS phenotype. PMID:24477106

Clinical Phenotypes and Prognostic Full-Field Electroretinographic Findings in Stargardt Disease

PubMed Central

ZAHID, SARWAR; JAYASUNDERA, THIRAN; RHOADES, WILLIAM; BRANHAM, KARI; KHAN, NAHEED; NIZIOL, LESLIE M.; MUSCH, DAVID C.; HECKENLIVELY, JOHN R.

2013-01-01

PURPOSE To investigate the relationships between clinical and full-field electroretinographic (ERG) findings and progressive loss of visual function in Stargardt disease. DESIGN Retrospective cohort study. METHODS We performed a retrospective review of data from 198 patients with Stargardt disease. Measures of visual function over time, including visual acuity, quantified Goldmann visual fields, and full-field ERG data were recorded. Data were analyzed using SAS statistical software. Subgroup analyses were performed on 148 patients with ERG phenotypic data, 46 patients with longitudinal visual field data, and 92 patients with identified ABCA4 mutations (46 with 1 mutation, and 47 with 2 or more mutations). RESULTS Of 46 patients with longitudinal visual field data, 8 patients with faster central scotoma progression rates had significantly worse scotopic B-wave amplitudes at their initial assessment than 20 patients with stable scotomata (P = .014) and were more likely to have atrophy beyond the arcades (P = .047). Overall, 47.3% of patients exhibited abnormal ERG results, with rod–cone dysfunction in 14.2% of patients, cone–rod dysfunction in 17.6% of patients, and isolated cone dysfunction in 15.5% of patients. Abnormal values in certain ERG parameters were associated significantly with (maximum-stimulation A- and B-wave amplitudes) or tended toward (photopic and scotopic B-wave amplitudes) a higher mean rate of central scotoma progression compared with those patients with normal ERG values. Scotoma size and ERG parameters differed significantly between those with a single mutation versus those with multiple mutations. CONCLUSIONS Full-field ERG examination provides clinically relevant information regarding the severity of Stargardt disease, likelihood of central scotoma expansion, and visual acuity deterioration. Patients also may exhibit an isolated cone dystrophy on ERG examination. PMID:23219216

CpG Island Methylator Phenotype Positive Tumors in the Absence of MLH1 Methylation Constitute a Distinct Subset of Duodenal Adenocarcinomas and Are Associated with Poor Prognosis

PubMed Central

Fu, Tao; Pappou, Emmanouil P.; Guzzetta, Angela A.; Jeschke, Jana; Kwak, Ruby; Dave, Pujan; Hooker, Craig M.; Morgan, Richard; Baylin, Stephen B.; Iacobuzio-Donahue, Christine A.; Wolfgang, Christopher L.; Ahuja, Nita

2012-01-01

Purpose Little information is available on genetic and epigenetic changes in duodenal adenocarcinomas. The purpose was to identify possible subsets of duodenal adenocarcinomas based on microsatellite instability (MSI), DNA methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, and prognosis. Experimental Design Demographics, tumor characteristics and survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS and BRAF mutations, MSI, MLH1 methylation and CpG island methylator phenotype (CIMP) status was performed. A Cox proportional hazard model was built to predict survival. Results CIMP+ was detected in 27 of 99 (27.3%) duodenal adenocarcinomas, and was associated with MSI (P = 0.011) and MLH1 methylation (P < 0.001), but not with KRAS mutations (P = 0.114), as compared to CIMP− tumors. No BRAF V600E mutation was detected. Among the CIMP+ tumors, 15 (55.6%) were CIMP+/MLH1-unmethylated (MLH1-U). Kaplan-Meier analysis showed tumors classified by CIMP, CIMP/MLH1 methylation status or CIMP/MSI status could predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), while CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a significant prognostic value regarding both OS (P < 0.001) and TTR (P = 0.023). Patients with CIMP+/MLH1-U tumors had the worst OS and TTR. Conclusions Our results demonstrate existence of CIMP in duodenal adenocarcinomas. The combination of CIMP+/MLH1-U appears to be independently associated with poor prognosis in patients with duodenal adenocarcinomas. This study also suggests that BRAF mutations are not involved in duodenal tumorigenesis, MSI or CIMP development. PMID:22825585

Progression of urothelial carcinoma in situ of the urinary bladder: a switch from luminal to basal phenotype and related therapeutic implications.

PubMed

Barth, Isabella; Schneider, Ursula; Grimm, Tobias; Karl, Alexander; Horst, David; Gaisa, Nadine T; Knüchel, Ruth; Garczyk, Stefan

2018-05-01

The stratification of bladder cancer into luminal and basal tumors has recently been introduced as a novel prognostic system in patient cohorts of muscle-invasive bladder cancer or high-grade papillary carcinomas. Using a representative immunohistochemistry panel, we analyzed luminal and basal marker expression in a large case series (n = 156) of urothelial carcinoma in situ (CIS), a precancerous lesion that frequently progresses to muscle-invasive disease. The majority of CIS cases was characterized by a positivity for luminal markers (aberrant cytokeratin (CK) 20 85% (132/156), GATA3 median Remmele score (score of staining intensity (0-3) multiplied with percentage of positive cells (0-4)): 12, estrogen receptor (ER) β Remmele score > 2: 88% (138/156), human epidermal growth factor receptor 2 (Her2) Dako score 3+ 32% (50/156), Her2 Dako score 2+ 33% (51/156)), and marginal expression of basal markers (CK5/6+ 2% (3/156), CK14+ 1% (2/156)). To further investigate phenotypic stability during disease progression, we compared 48 pairs of CIS and invasive tumors from the same biopsy. A highly significant loss of luminal marker expression (p < 0.001) was observed in the course of progression whereas an increase of basal marker expression (p < 0.01) was noted in the invasive compartment. Importantly, 91% of CIS cases demonstrated a positivity for at least one of the two predictive markers Her2 and ERβ, indicating that the analysis of Her2 and ERβ may help to identify CIS-patient subgroups prone to more efficient targeted treatment strategies. Larger prospective and biomarker-embedded clinical trials are needed to confirm and validate our preliminary findings.

Population-based genetic epidemiologic analysis of Chlamydia trachomatis serotypes and lack of association between ompA polymorphisms and clinical phenotypes.

PubMed

Millman, Kim; Black, Carolyn M; Stamm, Walter E; Jones, Robert B; Hook, Edward W; Martin, David H; Bolan, Gail; Tavaré, Simon; Dean, Deborah

2006-03-01

Chlamydia trachomatis is the leading cause of bacterial sexually transmitted diseases worldwide. Urogenital strains are classified into serotypes and genotypes based on the major outer membrane protein and its gene, ompA, respectively. Studies of the association of serotypes with clinical signs and symptoms have produced conflicting results while no studies have evaluated associations with ompA polymorphisms. We designed a population-based cross-sectional study of 344 men and women with urogenital chlamydial infections (excluding co-pathogen infections) presenting to clinics serving five U.S. cities from 1995 to 1997. Signs, symptoms and sequelae of chlamydial infection (mucopurulent cervicitis, vaginal or urethral discharge; dysuria; lower abdominal pain; abnormal vaginal bleeding; and pelvic inflammatory disease) were analyzed for associations with serotype and ompA polymorphisms. One hundred and fifty-three (44.5%) of 344 patients had symptoms consistent with urogenital chlamydial infection. Gender, reason for visit and city were significant independent predictors of symptom status. Men were 2.2 times more likely than women to report any symptoms (P=0.03) and 2.8 times more likely to report a urethral discharge than women were to report a vaginal discharge in adjusted analyses (P=0.007). Differences in serotype or ompA were not predictive except for an association between serotype F and pelvic inflammatory disease (P=0.046); however, the number of these cases was small. While there was no clinically prognostic value associated with serotype or ompA polymorphism for urogenital chlamydial infections except for serotype F, future studies might utilize multilocus genomic typing to identify chlamydial strains associated with clinical phenotypes.

BCL-2 system analysis identifies high-risk colorectal cancer patients.

PubMed

Lindner, Andreas U; Salvucci, Manuela; Morgan, Clare; Monsefi, Naser; Resler, Alexa J; Cremona, Mattia; Curry, Sarah; Toomey, Sinead; O'Byrne, Robert; Bacon, Orna; Stühler, Michael; Flanagan, Lorna; Wilson, Richard; Johnston, Patrick G; Salto-Tellez, Manuel; Camilleri-Broët, Sophie; McNamara, Deborah A; Kay, Elaine W; Hennessy, Bryan T; Laurent-Puig, Pierre; Van Schaeybroeck, Sandra; Prehn, Jochen H M

2017-12-01

The mitochondrial apoptosis pathway is controlled by an interaction of multiple BCL-2 family proteins, and plays a key role in tumour progression and therapy responses. We assessed the prognostic potential of an experimentally validated, mathematical model of BCL-2 protein interactions (DR_MOMP) in patients with stage III colorectal cancer (CRC). Absolute protein levels of BCL-2 family proteins were determined in primary CRC tumours collected from n=128 resected and chemotherapy-treated patients with stage III CRC. We applied DR_MOMP to categorise patients as high or low risk based on model outputs, and compared model outputs with known prognostic factors (T-stage, N-stage, lymphovascular invasion). DR_MOMP signatures were validated on protein of n=156 patients with CRC from the Cancer Genome Atlas (TCGA) project. High-risk stage III patients identified by DR_MOMP had an approximately fivefold increased risk of death compared with patients identified as low risk (HR 5.2, 95% CI 1.4 to 17.9, p=0.02). The DR_MOMP signature ranked highest among all molecular and pathological features analysed. The prognostic signature was validated in the TCGA colon adenocarcinoma (COAD) cohort (HR 4.2, 95% CI 1.1 to 15.6, p=0.04). DR_MOMP also further stratified patients identified by supervised gene expression risk scores into low-risk and high-risk categories. BCL-2-dependent signalling critically contributed to treatment responses in consensus molecular subtypes 1 and 3, linking for the first time specific molecular subtypes to apoptosis signalling. DR_MOMP delivers a system-based biomarker with significant potential as a prognostic tool for stage III CRC that significantly improves established histopathological risk factors. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Neurologic examination at 24–48 hours predicts functional outcomes in basilar artery occlusion stroke

PubMed Central

Rangaraju, Srikant; Jovin, Tudor G.; Frankel, Michael; Schonewille, Wouter J.; Algra, Ale; Kappelle, L. Jaap; Nogueira, Raul G.

2016-01-01

Background and Purpose Accurate long-term outcome prognostication in basilar artery occlusion (BAO) strokes may guide clinical management in the subacute stage. We determine the prognostic value of the follow-up neurologic examination using the NIH stroke scale (NIHSS) and identify 24–48 hours NIHSS risk categories in BAO patients. Methods Participants of an observational registry of radiologically-confirmed acute BAO (BASICS) with prospectively collected 24–48 hours NIHSS and 1-month modified Rankin Scale (mRS) scores were included. Uni- and multivariable modeling were performed to identify independent predictors of poor outcome. Predictive powers of baseline and 24–48 hour NIHSS for poor outcome (mRS 4–6) and 1-month mortality were determined by Receiver Operating Characteristic analyses. Classification and regression tree (CART) analysis was performed to identify risk groups. Results 376 of 619 BASICS participants were included of whom 65.4% had poor outcome. In multivariable analyses, 24–48 hours NIHSS (OR=1.28 [1.21–1.35]), history of minor stroke (OR=2.64 [1.04–6.74], time to treatment >6 hours (OR=3.07 [1.35–6.99]) and age (OR 1.02 [0.99–1.04] were retained in the final model as predictors of poor outcome. Prognostic power of 24–48 hours NIHSS was higher than baseline NIHSS for 1-month poor outcome (AUC 0.92 vs. 0.75) and mortality (AUC 0.85 vs. 0.72). CART analysis identified five 24–48 hour NIHSS risk categories with poor outcome rates of 9.4% (NIHSS 0–4), 36% (NIHSS 5–11), 84.3% (NIHSS 12–22), 96.1% (NIHSS 23–27) and 100% (NIHSS≥28). Conclusion 24–48 hour NIHSS accurately predicts 1-month poor outcome and mortality and represents a clinically valuable prognostic tool for the care of BAO patients. PMID:27586683

Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non–Small-Cell Lung Cancer and Brain Metastasis

PubMed Central

Johung, Kimberly L.; Yeh, Norman; Desai, Neil B.; Williams, Terence M.; Lautenschlaeger, Tim; Arvold, Nils D.; Ning, Matthew S.; Attia, Albert; Lovly, Christine M.; Goldberg, Sarah; Beal, Kathryn; Yu, James B.; Kavanagh, Brian D.; Chiang, Veronica L.; Camidge, D. Ross

2016-01-01

Purpose We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non–small-cell lung cancer (NSCLC) and brain metastasis. Patients and Methods A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling. Results Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001). Conclusion Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease. PMID:26438117

Workers' Compensation, Return to Work, and Lumbar Fusion for Spondylolisthesis.

PubMed

Anderson, Joshua T; Haas, Arnold R; Percy, Rick; Woods, Stephen T; Ahn, Uri M; Ahn, Nicholas U

2016-01-01

Lumbar fusion for spondylolisthesis is associated with consistent outcomes in the general population. However, workers' compensation is a risk factor for worse outcomes. Few studies have evaluated prognostic factors within this clinically distinct population. The goal of this study was to identify prognostic factors for return to work among patients with workers' compensation claims after fusion for spondylolisthesis. The authors used International Classification of Diseases, Ninth Revision, and Current Procedural Terminology codes to identify 686 subjects from the Ohio Bureau of Workers' Compensation who underwent fusion for spondylolisthesis from 1993 to 2013. Positive return to work status was recorded in patients who returned to work within 2 years of fusion and remained working for longer than 6 months. The criteria for return to work were met by 29.9% (n=205) of subjects. The authors used multivariate logistic regression analysis to identify prognostic factors for return to work. Negative preoperative prognostic factors for postoperative return to work included: out of work for longer than 1 year before fusion (P<.001; odds ratio [OR], 0.16); depression (P=.007; OR<0.01); long-term opioid analgesic use (P=.006; OR, 0.41); lumbar stenosis (P=.043; OR, 0.55); and legal representation (P=.042; OR, 0.63). Return to work rates associated with these factors were 9.7%, 0.0%, 10.0%, 29.2%, and 25.0%, respectively. If these subjects were excluded, the return to work rate increased to 60.4%. The 70.1% (n=481) of subjects who did not return to work had markedly worse outcomes, shown by higher medical costs, chronic opioid dependence, and higher rates of failed back syndrome, total disability, and additional surgery. Psychiatric comorbidity increased after fusion but was much higher in those who did not return to work. Future studies are needed to identify how to better facilitate return to work among similar patients with workers' compensation claims. Copyright 2016, SLACK Incorporated.

Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network

PubMed Central

Pendergrass, Sarah A.; Brown-Gentry, Kristin; Dudek, Scott; Frase, Alex; Torstenson, Eric S.; Goodloe, Robert; Ambite, Jose Luis; Avery, Christy L.; Buyske, Steve; Bůžková, Petra; Deelman, Ewa; Fesinmeyer, Megan D.; Haiman, Christopher A.; Heiss, Gerardo; Hindorff, Lucia A.; Hsu, Chu-Nan; Jackson, Rebecca D.; Kooperberg, Charles; Le Marchand, Loic; Lin, Yi; Matise, Tara C.; Monroe, Kristine R.; Moreland, Larry; Park, Sungshim L.; Reiner, Alex; Wallace, Robert; Wilkens, Lynn R.; Crawford, Dana C.; Ritchie, Marylyn D.

2013-01-01

Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype–phenotype associations, 26 represented phenotypes closely related to previously known genotype–phenotype associations, and 33 represented potentially novel genotype–phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits. PMID:23382687

Prognostic factors of whiplash-associated disorders: a systematic review of prospective cohort studies.

PubMed

Scholten-Peeters, Gwendolijne G M; Verhagen, Arianne P; Bekkering, Geertruida E; van der Windt, Daniëlle A W M; Barnsley, Les; Oostendorp, Rob A B; Hendriks, Erik J M

2003-07-01

We present a systematic review of prospective cohort studies. Our aim was to assess prognostic factors associated with functional recovery of patients with whiplash injuries. The failure of some patients to recover following whiplash injury has been linked to a number of prognostic factors. However, there is some inconsistency in the literature and there have been no systematic attempts to analyze the level of evidence for prognostic factors in whiplash recovery. Studies were selected for inclusion following a comprehensive search of MEDLINE, EMBASE, CINAHL, the database of the Dutch Institute of Allied Health Professions up until April 2002 and hand searches of the reference lists of retrieved articles. Studies were selected if the objective was to assess prognostic factors associated with recovery; the design was a prospective cohort study; the study population included at least an identifiable subgroup of patients suffering from a whiplash injury; and the paper was a full report published in English, German, French or Dutch. The methodological quality was independently assessed by two reviewers. A study was considered to be of 'high quality' if it satisfied at least 50% of the maximum available quality score. Two independent reviewers extracted data and the association between prognostic factors and functional recovery was calculated in terms of risk estimates. Fifty papers reporting on twenty-nine cohorts were included in the review. Twelve cohorts were considered to be of 'high quality'. Because of the heterogeneity of patient selection, type of prognostic factors and outcome measures, no statistical pooling was able to be performed. Strong evidence was found for high initial pain intensity being an adverse prognostic factor. There was strong evidence that for older age, female gender, high acute psychological response, angular deformity of the neck, rear-end collision, and compensation not being associated with an adverse prognosis. Several physical (e.g. restricted range of motion, high number of complaints), psychosocial (previous psychological problems), neuropsychosocial factors (nervousness), crash related (e.g. accident on highway) and treatment related factors (need to resume physiotherapy) showed limited prognostic value for functional recovery. High initial pain intensity is an important predictor for delayed functional recovery for patients with whiplash injury. Often mentioned factors like age, gender and compensation do not seem to be of prognostic value. Scientific information about prognostic factors can guide physicians or other care providers to direct treatment and to probably prevent chronicity.

Divergent sensory phenotypes in nonspecific arm pain: comparisons with cervical radiculopathy.

PubMed

Moloney, Niamh; Hall, Toby; Doody, Catherine

2015-02-01

To investigate whether distinct sensory phenotypes were identifiable in individuals with nonspecific arm pain (NSAP) and whether these differed from those in people with cervical radiculopathy. A secondary question considered whether the frequency of features of neuropathic pain, kinesiophobia, high pain ratings, hyperalgesia, and allodynia differed according to subgroups of sensory phenotypes. Cross-sectional study. Higher education institution. Forty office workers with NSAP, 17 people with cervical radiculopathy, and 40 age- and sex-matched healthy controls (N=97). Not applicable. Participants were assessed using quantitative sensory testing (QST) comprising thermal and vibration detection thresholds and thermal and pressure pain thresholds; clinical examination; and relevant questionnaires. Sensory phenotypes were identified for each individual in the patient groups using z-score transformation of the QST data. Individuals with NSAP and cervical radiculopathy present with a spectrum of sensory abnormalities; a dominant sensory phenotype was not identifiable in individuals with NSAP. No distinct pattern between clinical features and questionnaire results across sensory phenotypes was identified in either group. When considering sensory phenotypes, neither individuals with NSAP nor individuals with cervical radiculopathy should be considered homogeneous. Therefore, people with either condition may warrant different intervention approaches according to their individual sensory phenotype. Issues relating to the clinical identification of sensory hypersensitivity and the validity of QST are highlighted. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Characterization of Novel Genes Within 8P11-12 Amplicon in Breast Cancer

DTIC Science & Technology

2007-06-01

C-myc amplification in breast cancer: a meta - analysis of its occurrence and prognostic relevance. Br J Cancer, 83: 1688-1695, 2000. 2. Hui, R...Nass SJ, Dickson RB, Trock BJ. C-myc amplification in breast cancer: a meta - analysis of its occurrence and prognostic relevance. Br J Cancer 2000;83...a detailed genomic and expression analysis of the 8p11-p12 amplicon in breast cancer cell lines and identified several novel candidate genes

TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis.

PubMed

Cyr, A R; Kulak, M V; Park, J M; Bogachek, M V; Spanheimer, P M; Woodfield, G W; White-Baer, L S; O'Malley, Y Q; Sugg, S L; Olivier, A K; Zhang, W; Domann, F E; Weigel, R J

2015-01-22

Molecular subtypes of breast cancer are characterized by distinct patterns of gene expression that are predictive of outcome and response to therapy. The luminal breast cancer subtypes are defined by the expression of estrogen receptor-alpha (ERα)-associated genes, many of which are directly responsive to the transcription factor activator protein 2C (TFAP2C). TFAP2C participates in a gene regulatory network controlling cell growth and differentiation during ectodermal development and regulating ESR1/ERα and other luminal cell-associated genes in breast cancer. TFAP2C has been established as a prognostic factor in human breast cancer, however, its role in the establishment and maintenance of the luminal cell phenotype during carcinogenesis and mammary gland development have remained elusive. Herein, we demonstrate a critical role for TFAP2C in maintaining the luminal phenotype in human breast cancer and in influencing the luminal cell phenotype during normal mammary development. Knockdown of TFAP2C in luminal breast carcinoma cells induced epithelial-mesenchymal transition with morphological and phenotypic changes characterized by a loss of luminal-associated gene expression and a concomitant gain of basal-associated gene expression. Conditional knockout of the mouse homolog of TFAP2C, Tcfap2c, in mouse mammary epithelium driven by MMTV-Cre promoted aberrant growth of the mammary tree leading to a reduction in the CD24(hi)/CD49f(mid) luminal cell population and concomitant gain of the CD24(mid)/CD49f(hi) basal cell population at maturity. Our results establish TFAP2C as a key transcriptional regulator for maintaining the luminal phenotype in human breast carcinoma. Furthermore, Tcfap2c influences development of the luminal cell type during mammary development. The data suggest that TFAP2C has an important role in regulated luminal-specific genes and may be a viable therapeutic target in breast cancer.

Identification of a neuronal transcription factor network involved in medulloblastoma development.

PubMed

Lastowska, Maria; Al-Afghani, Hani; Al-Balool, Haya H; Sheth, Harsh; Mercer, Emma; Coxhead, Jonathan M; Redfern, Chris P F; Peters, Heiko; Burt, Alastair D; Santibanez-Koref, Mauro; Bacon, Chris M; Chesler, Louis; Rust, Alistair G; Adams, David J; Williamson, Daniel; Clifford, Steven C; Jackson, Michael S

2013-07-11

Medulloblastomas, the most frequent malignant brain tumours affecting children, comprise at least 4 distinct clinicogenetic subgroups. Aberrant sonic hedgehog (SHH) signalling is observed in approximately 25% of tumours and defines one subgroup. Although alterations in SHH pathway genes (e.g. PTCH1, SUFU) are observed in many of these tumours, high throughput genomic analyses have identified few other recurring mutations. Here, we have mutagenised the Ptch+/- murine tumour model using the Sleeping Beauty transposon system to identify additional genes and pathways involved in SHH subgroup medulloblastoma development. Mutagenesis significantly increased medulloblastoma frequency and identified 17 candidate cancer genes, including orthologs of genes somatically mutated (PTEN, CREBBP) or associated with poor outcome (PTEN, MYT1L) in the human disease. Strikingly, these candidate genes were enriched for transcription factors (p=2x10-5), the majority of which (6/7; Crebbp, Myt1L, Nfia, Nfib, Tead1 and Tgif2) were linked within a single regulatory network enriched for genes associated with a differentiated neuronal phenotype. Furthermore, activity of this network varied significantly between the human subgroups, was associated with metastatic disease, and predicted poor survival specifically within the SHH subgroup of tumours. Igf2, previously implicated in medulloblastoma, was the most differentially expressed gene in murine tumours with network perturbation, and network activity in both mouse and human tumours was characterised by enrichment for multiple gene-sets indicating increased cell proliferation, IGF signalling, MYC target upregulation, and decreased neuronal differentiation. Collectively, our data support a model of medulloblastoma development in SB-mutagenised Ptch+/- mice which involves disruption of a novel transcription factor network leading to Igf2 upregulation, proliferation of GNPs, and tumour formation. Moreover, our results identify rational therapeutic targets for SHH subgroup tumours, alongside prognostic biomarkers for the identification of poor-risk SHH patients.

Integrative network analysis unveils convergent molecular pathways in Parkinson's disease and diabetes.

PubMed

Santiago, Jose A; Potashkin, Judith A

2013-01-01

Shared dysregulated pathways may contribute to Parkinson's disease and type 2 diabetes, chronic diseases that afflict millions of people worldwide. Despite the evidence provided by epidemiological and gene profiling studies, the molecular and functional networks implicated in both diseases, have not been fully explored. In this study, we used an integrated network approach to investigate the extent to which Parkinson's disease and type 2 diabetes are linked at the molecular level. Using a random walk algorithm within the human functional linkage network we identified a molecular cluster of 478 neighboring genes closely associated with confirmed Parkinson's disease and type 2 diabetes genes. Biological and functional analysis identified the protein serine-threonine kinase activity, MAPK cascade, activation of the immune response, and insulin receptor and lipid signaling as convergent pathways. Integration of results from microarrays studies identified a blood signature comprising seven genes whose expression is dysregulated in Parkinson's disease and type 2 diabetes. Among this group of genes, is the amyloid precursor protein (APP), previously associated with neurodegeneration and insulin regulation. Quantification of RNA from whole blood of 192 samples from two independent clinical trials, the Harvard Biomarker Study (HBS) and the Prognostic Biomarker Study (PROBE), revealed that expression of APP is significantly upregulated in Parkinson's disease patients compared to healthy controls. Assessment of biomarker performance revealed that expression of APP could distinguish Parkinson's disease from healthy individuals with a diagnostic accuracy of 80% in both cohorts of patients. These results provide the first evidence that Parkinson's disease and diabetes are strongly linked at the molecular level and that shared molecular networks provide an additional source for identifying highly sensitive biomarkers. Further, these results suggest for the first time that increased expression of APP in blood may modulate the neurodegenerative phenotype in type 2 diabetes patients.

Biological significance of long non-coding RNA FTX expression in human colorectal cancer

PubMed Central

Guo, Xiao-Bo; Hua, Zhu; Li, Chen; Peng, Li-Pan; Wang, Jing-Shen; Wang, Bo; Zhi, Qiao-Ming

2015-01-01

The purpose of this study was to determine the expression of long non-coding RNA (lncRNA) FTX and analyze its prognostic and biological significance in colorectal cancer (CRC). A quantitative reverse transcription PCR was performed to detect the expression of long non-coding RNA FTX in 35 pairs of colorectal cancer and corresponding noncancerous tissues. The expression of long non-coding RNA FTX was detected in 187 colorectal cancer tissues and its correlations with clinicopathological factors of patients were examined. Univariate and multivariate analyses were performed to analyze the prognostic significance of Long Non-coding RNA FTX expression. The effects of long non-coding RNA FTX expression on malignant phenotypes of colorectal cancer cells and its possible biological significances were further determined. Long non-coding RNA FTX was significantly upregulated in colorectal cancer tissues, and low long non-coding RNA FTX expression was significantly correlated with differentiation grade, lymph vascular invasion, and clinical stage. Patients with high long non-coding RNA FTX showed poorer overall survival than those with low long non-coding RNA FTX. Multivariate analyses indicated that status of long non-coding RNA FTX was an independent prognostic factor for patients. Functional analyses showed that upregulation of long non-coding RNA FTX significantly promoted growth, migration, invasion, and increased colony formation in colorectal cancer cells. Therefore, long non-coding RNA FTX may be a potential biomarker for predicting the survival of colorectal cancer patients and might be a molecular target for treatment of human colorectal cancer. PMID:26629053

MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program

PubMed Central

Xu-Monette, Zijun Y.; Møller, Michael B.; Tzankov, Alexander; Montes-Moreno, Santiago; Hu, Wenwei; Manyam, Ganiraju C.; Kristensen, Louise; Fan, Lei; Visco, Carlo; Dybkær, Karen; Chiu, April; Tam, Wayne; Zu, Youli; Bhagat, Govind; Richards, Kristy L.; Hsi, Eric D.; Choi, William W. L.; van Krieken, J. Han; Huang, Qin; Huh, Jooryung; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andrés J. M.; Wu, Lin; Zhao, Xiaoying; Bueso-Ramos, Carlos E.; Wang, Sa A.; Go, Ronald S.; Li, Yong; Winter, Jane N.; Medeiros, L. Jeffrey

2013-01-01

MDM2 is a key negative regulator of the tumor suppressor p53, however, the prognostic significance of MDM2 overexpression in diffuse large B-cell lymphoma (DLBCL) has not been defined convincingly. In a p53 genetically–defined large cohort of de novo DLBCL patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, we assessed MDM2 and p53 expression by immunohistochemistry (n = 478), MDM2 gene amplification by fluorescence in situ hybridization (n = 364), and a single nucleotide polymorphism in the MDM2 promoter, SNP309, by SNP genotyping assay (n = 108). Our results show that MDM2 overexpression, unlike p53 overexpression, is not a significant prognostic factor in overall DLBCL. Both MDM2 and p53 overexpression do not predict for an adverse clinical outcome in patients with wild-type p53 but predicts for significantly poorer survival in patients with mutated p53. Variable p53 activities may ultimately determine the survival differences, as suggested by the gene expression profiling analysis. MDM2 amplification was observed in 3 of 364 (0.8%) patients with high MDM2 expression. The presence of SNP309 did not correlate with MDM2 expression and survival. This study indicates that evaluation of MDM2 and p53 expression correlating with TP53 genetic status is essential to assess their prognostic significance and is important for designing therapeutic strategies that target the MDM2-p53 interaction. PMID:23982177

The roles of pathology in targeted therapy of women with gynecologic cancers.

PubMed

Murali, Rajmohan; Grisham, Rachel N; Soslow, Robert A

2018-01-01

The role of the pathologist in the multidisciplinary management of women with gynecologic cancer has evolved substantially over the past decade. Pathologists' evaluation of parameters such as pathologic stage, histologic subtype, grade and microsatellite instability, and their identification of patients at risk for Lynch syndrome have become essential components of diagnosis, prognostic assessment and determination of optimal treatment of affected women. Despite the use of multimodality treatment and combination cytotoxic chemotherapy, the prognosis of women with advanced-stage gynecologic cancer is often poor. Therefore, expanding the arsenal of available systemic therapies with targeted therapeutic agents is appealing. Anti-angiogenic therapies, immunotherapy and poly ADP ribose polymerase (PARP) inhibitors are now routinely used for the treatment of advanced gynecologic cancer, and many more are under investigation. Pathologists remain important in the clinical management of patients with targeted therapy, by identifying potentially targetable tumors on the basis of their pathologic phenotype, by assessing biomarkers that are predictive of response to targeted therapy (e.g. microsatellite instability, PD1/PDL1 expression), and by monitoring treatment response and resistance. Pathologists are also vital to research efforts exploring novel targeted therapies by identifying homogenous subsets of tumors for more reliable and meaningful analyses, and by confirming expression in tumor tissues of novel targets identified in genomic, epigenetic or other screening studies. In the era of precision gynecologic oncology, the roles of pathologists in the discovery, development and implementation of targeted therapeutic strategies remain as central as they are for traditional (surgery-chemotherapy-radiotherapy) management of women with gynecologic cancers. Copyright © 2017 Elsevier Inc. All rights reserved.

Poorly Differentiated Medullary Phenotype Predicts Poor Survival in Early Lymph Node-Negative Gastro-Esophageal Adenocarcinomas.

PubMed

Treese, Christoph; Sanchez, Pedro; Grabowski, Patricia; Berg, Erika; Bläker, Hendrik; Kruschewski, Martin; Haase, Oliver; Hummel, Michael; Daum, Severin

2016-01-01

5-year survival rate in patients with early adenocarcinoma of the gastro-esophageal junction or stomach (AGE/S) in Caucasian patients is reported to be 60-80%. We aimed to identify prognostic markers for patients with UICC-I without lymph-node involvement (N0). Clinical data and tissue specimen from patients with AGE/S stage UICC-I-N0, treated by surgery only, were collected retrospectively. Tumor size, lymphatic vessel or vein invasion, grading, classification systems (WHO, Lauren, Ming), expression of BAX, BCL-2, CDX2, Cyclin E, E-cadherin, Ki-67, TP53, TP21, SHH, Survivin, HIF1A, TROP2 and mismatch repair deficiency were analyzed using tissue microarrays and correlated with overall and tumor related survival. 129 patients (48 female) with a mean follow-up of 129.1 months were identified. 5-year overall survival was 83.9%, 5-year tumor related survival was 95.1%. Poorly differentiated medullary cancer subtypes (p<0.001) and positive vein invasion (p<0.001) were identified as risk factors for decreased overall-and tumor related survival. Ki-67 (p = 0.012) and TP53 mutation (p = 0.044) were the only immunohistochemical markers associated with worse overall survival but did not reach significance for decreased tumor related survival. In the presented study patients with AGE/S in stage UICC-I-N0 had a better prognosis as previously reported for Caucasian patients. Poorly differentiated medullary subtype was associated with reduced survival and should be considered when studying prognosis in these patients.

Glutathione S-transferase Pi expression in invasive breast cancer and its relation with the clinical outcome.

PubMed

Franco, R L; Schenka, N G M; Schenka, A A A; Rezende, L F; Gurgel, M S C

2012-01-01

Glutathione S-transferase (GST) is a cytosolic enzymatic system involved in cellular detoxifying process. In vitro studies have shown that the presence of this enzymatic system in breast carcinoma cells can accelerate the elimination of drugs commonly used in chemotherapy, thereby decreasing its efficacy. The aim of the present study was to evaluate the association between GST Pi expression by breast carcinoma cells and disease-free and overall survival. Ninety-five female patients with invasive breast carcinoma submitted to surgical treatment and adjuvant chemotherapy from January, 1995 to June, 1997 and followed until August, 2006 were evaluated. The expression of GST Pi in breast carcinoma cells, determined by immunohistochemistry, was correlated with several clinical and pathological parameters of prognostic significance. There were 36 (37.9%) GST Pi-positive cases. GST Pi immunoexpression was not significantly correlated with patient's age, histological tumor type, clinical stage, hormone receptor status and survival. On the other hand, GST Pi positivity showed a significant correlation with a lower histological grade/C-erb-B2 negative breast carcinoma phenotype. The findings suggest that GST Pi expression does not constitute a satisfactory prognostic factor in breast cancer.

The non-small cell lung cancer immune landscape: emerging complexity, prognostic relevance and prospective significance in the context of immunotherapy.

PubMed

Anichini, Andrea; Tassi, Elena; Grazia, Giulia; Mortarini, Roberta

2018-06-01

Immunotherapy of non-small cell lung cancer (NSCLC), by immune checkpoint inhibitors, has profoundly improved the clinical management of advanced disease. However, only a fraction of patients respond and no effective predictive factors have been defined. Here, we discuss the prospects for identification of such predictors of response to immunotherapy, by fostering an in-depth analysis of the immune landscape of NSCLC. The emerging picture, from several recent studies, is that the immune contexture of NSCLC lesions is a complex and heterogeneous feature, as documented by analysis for frequency, phenotype and spatial distribution of innate and adaptive immune cells, and by characterization of functional status of inhibitory receptor + T cells. The complexity of the immune landscape of NSCLC stems from the interaction of several factors, including tumor histology, molecular subtype, main oncogenic drivers, nonsynonymous mutational load, tumor aneuploidy, clonal heterogeneity and tumor evolution, as well as the process of epithelial-mesenchymal transition. All these factors contribute to shape NSCLC immune profiles that have clear prognostic significance. An integrated analysis of the immune and molecular profile of the neoplastic lesions may allow to define the potential predictive role of the immune landscape for response to immunotherapy.

Molecular classification of breast cancer: what the pathologist needs to know.

PubMed

Rakha, Emad A; Green, Andrew R

2017-02-01

Breast cancer is a heterogeneous disease featuring distinct histological, molecular and clinical phenotypes. Although traditional classification systems utilising clinicopathological and few molecular markers are well established and validated, they remain insufficient to reflect the diverse biological and clinical heterogeneity of breast cancer. Advancements in high-throughput molecular techniques and bioinformatics have contributed to the improved understanding of breast cancer biology, refinement of molecular taxonomies and the development of novel prognostic and predictive molecular assays. Application of such technologies is already underway, and is expected to change the way we manage breast cancer. Despite the enormous amount of work that has been carried out to develop and refine breast cancer molecular prognostic and predictive assays, molecular testing is still in evolution. Pathologists should be aware of the new technology and be ready for the challenge. In this review, we provide an update on the application of molecular techniques with regard to breast cancer diagnosis, prognosis and outcome prediction. The current contribution of emerging technology to our understanding of breast cancer is also highlighted. Copyright © 2016 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

The Diagnostic and Prognostic Role of microRNA in Colorectal Cancer - a Comprehensive review.

PubMed

Mazeh, Haggi; Mizrahi, Ido; Ilyayev, Nadia; Halle, David; Brücher, Bjoern; Bilchik, Anton; Protic, Mladjan; Daumer, Martin; Stojadinovic, Alexander; Itzhak, Avital; Nissan, Aviram

2013-01-01

The discovery of microRNA, a group of regulatory short RNA fragments, has added a new dimension to the diagnosis and management of neoplastic diseases. Differential expression of microRNA in a unique pattern in a wide range of tumor types enables researches to develop a microRNA-based assay for source identification of metastatic disease of unknown origin. This is just one example of many microRNA-based cancer diagnostic and prognostic assays in various phases of clinical research.Since colorectal cancer (CRC) is a phenotypic expression of multiple molecular pathways including chromosomal instability (CIN), micro-satellite instability (MIS) and CpG islands promoter hypermethylation (CIMP), there is no one-unique pattern of microRNA expression expected in this disease and indeed, there are multiple reports published, describing different patterns of microRNA expression in CRC.The scope of this manuscript is to provide a comprehensive review of the scientific literature describing the dysregulation of and the potential role for microRNA in the management of CRC. A Pubmed search was conducted using the following MeSH terms, "microRNA" and "colorectal cancer". Of the 493 publications screened, there were 57 papers describing dysregulation of microRNA in CRC.

Characterisation of male breast cancer: a descriptive biomarker study from a large patient series.

PubMed

Humphries, Matthew P; Sundara Rajan, Sreekumar; Honarpisheh, Hedieh; Cserni, Gabor; Dent, Jo; Fulford, Laura; Jordan, Lee B; Jones, J Louise; Kanthan, Rani; Litwiniuk, Maria; Di Benedetto, Anna; Mottolese, Marcella; Provenzano, Elena; Shousha, Sami; Stephens, Mark; Kulka, Janina; Ellis, Ian O; Titloye, Akinwale N; Hanby, Andrew M; Shaaban, Abeer M; Speirs, Valerie

2017-03-28

Male breast cancer (MBC) is rare. We assembled 446 MBCs on tissue microarrays and assessed clinicopathological information, together with data from 15 published studies, totalling 1984 cases. By immunohistochemistry we investigated 14 biomarkers (ERα, ERβ1, ERβ2, ERβ5, PR, AR, Bcl-2, HER2, p53, E-cadherin, Ki67, survivin, prolactin, FOXA1) for survival impact. The main histological subtype in our cohort and combined analyses was ductal (81%, 83%), grade 2; (40%, 44%), respectively. Cases were predominantly ERα (84%, 82%) and PR positive (74%, 71%), respectively, with HER2 expression being infrequent (2%, 10%), respectively. In our cohort, advanced age (>67) was the strongest predictor of overall (OS) and disease free survival (DFS) (p = 0.00001; p = 0.01, respectively). Node positivity negatively impacted DFS (p = 0.04). FOXA1 p = 0.005) and AR p = 0.009) were both positively prognostic for DFS, remaining upon multivariate analysis. Network analysis showed ERα, AR and FOXA1 significantly correlated. In summary, the principle phenotype of MBC was luminal A, ductal, grade 2. In ERα+ MBC, only AR had prognostic significance, suggesting AR blockade could be employed therapeutically.

Prediction of risk of recurrence of venous thromboembolism following treatment for a first unprovoked venous thromboembolism: systematic review, prognostic model and clinical decision rule, and economic evaluation.

PubMed

Ensor, Joie; Riley, Richard D; Jowett, Sue; Monahan, Mark; Snell, Kym Ie; Bayliss, Susan; Moore, David; Fitzmaurice, David

2016-02-01

Unprovoked first venous thromboembolism (VTE) is defined as VTE in the absence of a temporary provoking factor such as surgery, immobility and other temporary factors. Recurrent VTE in unprovoked patients is highly prevalent, but easily preventable with oral anticoagulant (OAC) therapy. The unprovoked population is highly heterogeneous in terms of risk of recurrent VTE. The first aim of the project is to review existing prognostic models which stratify individuals by their recurrence risk, therefore potentially allowing tailored treatment strategies. The second aim is to enhance the existing research in this field, by developing and externally validating a new prognostic model for individual risk prediction, using a pooled database containing individual patient data (IPD) from several studies. The final aim is to assess the economic cost-effectiveness of the proposed prognostic model if it is used as a decision rule for resuming OAC therapy, compared with current standard treatment strategies. Standard systematic review methodology was used to identify relevant prognostic model development, validation and cost-effectiveness studies. Bibliographic databases (including MEDLINE, EMBASE and The Cochrane Library) were searched using terms relating to the clinical area and prognosis. Reviewing was undertaken by two reviewers independently using pre-defined criteria. Included full-text articles were data extracted and quality assessed. Critical appraisal of included full texts was undertaken and comparisons made of model performance. A prognostic model was developed using IPD from the pooled database of seven trials. A novel internal-external cross-validation (IECV) approach was used to develop and validate a prognostic model, with external validation undertaken in each of the trials iteratively. Given good performance in the IECV approach, a final model was developed using all trials data. A Markov patient-level simulation was used to consider the economic cost-effectiveness of using a decision rule (based on the prognostic model) to decide on resumption of OAC therapy (or not). Three full-text articles were identified by the systematic review. Critical appraisal identified methodological and applicability issues; in particular, all three existing models did not have external validation. To address this, new prognostic models were sought with external validation. Two potential models were considered: one for use at cessation of therapy (pre D-dimer), and one for use after cessation of therapy (post D-dimer). Model performance measured in the external validation trials showed strong calibration performance for both models. The post D-dimer model performed substantially better in terms of discrimination (c = 0.69), better separating high- and low-risk patients. The economic evaluation identified that a decision rule based on the final post D-dimer model may be cost-effective for patients with predicted risk of recurrence of over 8% annually; this suggests continued therapy for patients with predicted risks ≥ 8% and cessation of therapy otherwise. The post D-dimer model performed strongly and could be useful to predict individuals' risk of recurrence at any time up to 2-3 years, thereby aiding patient counselling and treatment decisions. A decision rule using this model may be cost-effective for informing clinical judgement and patient opinion in treatment decisions. Further research may investigate new predictors to enhance model performance and aim to further externally validate to confirm performance in new, non-trial populations. Finally, it is essential that further research is conducted to develop a model predicting bleeding risk on therapy, to manage the balance between the risks of recurrence and bleeding. This study is registered as PROSPERO CRD42013003494. The National Institute for Health Research Health Technology Assessment programme.

Overeating phenotypes in overweight and obese children.

PubMed

Boutelle, Kerri N; Peterson, Carol B; Crosby, Ross D; Rydell, Sarah A; Zucker, Nancy; Harnack, Lisa

2014-05-01

The purpose of this study was to identify overeating phenotypes and their correlates in overweight and obese children. One hundred and seventeen treatment-seeking overweight and obese 8-12year-old children and their parents completed the study. Children completed an eating in the absence of hunger (EAH) paradigm, the Eating Disorder Examination interview, and measurements of height and weight. Parents and children completed questionnaires that evaluated satiety responsiveness, food responsiveness, negative affect eating, external eating and eating in the absence of hunger. Latent profile analysis was used to identify heterogeneity in overeating phenotypes in the child participants. Latent classes were then compared on measures of demographics, obesity status and nutritional intake. Three latent classes of overweight and obese children were identified: High Satiety Responsive, High Food Responsive, and Moderate Satiety and Food Responsive. Results indicated that the High Food Responsive group had higher BMI and BMI-Z scores compared to the High Satiety Responsive group. No differences were found among classes in demographics or nutritional intake. This study identified three overeating phenotypes, supporting the heterogeneity of eating patterns associated with overweight and obesity in treatment-seeking children. These finding suggest that these phenotypes can potentially be used to identify high risk groups, inform prevention and intervention targets, and develop specific treatments for these behavioral phenotypes. Copyright © 2014. Published by Elsevier Ltd.

Discovery of prognostic biomarkers for predicting lung cancer metastasis using microarray and survival data.

PubMed

Huang, Hui-Ling; Wu, Yu-Chung; Su, Li-Jen; Huang, Yun-Ju; Charoenkwan, Phasit; Chen, Wen-Liang; Lee, Hua-Chin; Chu, William Cheng-Chung; Ho, Shinn-Ying

2015-02-21

Few studies have investigated prognostic biomarkers of distant metastases of lung cancer. One of the central difficulties in identifying biomarkers from microarray data is the availability of only a small number of samples, which results overtraining. Recently obtained evidence reveals that epithelial-mesenchymal transition (EMT) of tumor cells causes metastasis, which is detrimental to patients' survival. This work proposes a novel optimization approach to discovering EMT-related prognostic biomarkers to predict the distant metastasis of lung cancer using both microarray and survival data. This weighted objective function maximizes both the accuracy of prediction of distant metastasis and the area between the disease-free survival curves of the non-distant and distant metastases. Seventy-eight patients with lung cancer and a follow-up time of 120 months are used to identify a set of gene markers and an independent cohort of 26 patients is used to evaluate the identified biomarkers. The medical records of the 78 patients show a significant difference between the disease-free survival times of the 37 non-distant- and the 41 distant-metastasis patients. The experimental results thus obtained are as follows. 1) The use of disease-free survival curves can compensate for the shortcoming of insufficient samples and greatly increase the test accuracy by 11.10%; and 2) the support vector machine with a set of 17 transcripts, such as CCL16 and CDKN2AIP, can yield a leave-one-out cross-validation accuracy of 93.59%, a test accuracy of 76.92%, a large disease-free survival area of 74.81%, and a mean survival prediction error of 3.99 months. The identified putative biomarkers are examined using related studies and signaling pathways to reveal the potential effectiveness of the biomarkers in prospective confirmatory studies. The proposed new optimization approach to identifying prognostic biomarkers by combining multiple sources of data (microarray and survival) can facilitate the accurate selection of biomarkers that are most relevant to the disease while solving the problem of insufficient samples.

Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis.

PubMed

Pichler, Martin; Stiegelbauer, Verena; Vychytilova-Faltejskova, Petra; Ivan, Cristina; Ling, Hui; Winter, Elke; Zhang, Xinna; Goblirsch, Matthew; Wulf-Goldenberg, Annika; Ohtsuka, Masahisa; Haybaeck, Johannes; Svoboda, Marek; Okugawa, Yoshinaga; Gerger, Armin; Hoefler, Gerald; Goel, Ajay; Slaby, Ondrej; Calin, George Adrian

2017-03-01

Purpose: Characterization of colorectal cancer transcriptome by high-throughput techniques has enabled the discovery of several differentially expressed genes involving previously unreported miRNA abnormalities. Here, we followed a systematic approach on a global scale to identify miRNAs as clinical outcome predictors and further validated them in the clinical and experimental setting. Experimental Design: Genome-wide miRNA sequencing data of 228 colorectal cancer patients from The Cancer Genome Atlas dataset were analyzed as a screening cohort to identify miRNAs significantly associated with survival according to stringent prespecified criteria. A panel of six miRNAs was further validated for their prognostic utility in a large independent validation cohort ( n = 332). In situ hybridization and functional experiments in a panel of colorectal cancer cell lines and xenografts further clarified the role of clinical relevant miRNAs. Results: Six miRNAs (miR-92b-3p, miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p, and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR-188-3p expression proves to be an independent prognostic factor [screening cohort: HR = 4.137; 95% confidence interval (CI), 1.568-10.917; P = 0.004; validation cohort: HR = 1.538; 95% CI, 1.107-2.137; P = 0.010, respectively]. Forced miR-188-3p expression increased migratory behavior of colorectal cancer cells in vitro and metastases formation in vivo ( P < 0.05). The promigratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in colorectal cancer cell migration. Conclusions: miR-188-3p is a novel independent prognostic factor in colorectal cancer patients, which can be partly explained by its effect on MLLT4 expression and migration of cancer cells. Clin Cancer Res; 23(5); 1323-33. ©2016 AACR . ©2016 American Association for Cancer Research.

Development of Type 2 Diabetes Mellitus Phenotyping Framework Using Expert Knowledge and Machine Learning Approach.

PubMed

Kagawa, Rina; Kawazoe, Yoshimasa; Ida, Yusuke; Shinohara, Emiko; Tanaka, Katsuya; Imai, Takeshi; Ohe, Kazuhiko

2017-07-01

Phenotyping is an automated technique that can be used to distinguish patients based on electronic health records. To improve the quality of medical care and advance type 2 diabetes mellitus (T2DM) research, the demand for T2DM phenotyping has been increasing. Some existing phenotyping algorithms are not sufficiently accurate for screening or identifying clinical research subjects. We propose a practical phenotyping framework using both expert knowledge and a machine learning approach to develop 2 phenotyping algorithms: one is for screening; the other is for identifying research subjects. We employ expert knowledge as rules to exclude obvious control patients and machine learning to increase accuracy for complicated patients. We developed phenotyping algorithms on the basis of our framework and performed binary classification to determine whether a patient has T2DM. To facilitate development of practical phenotyping algorithms, this study introduces new evaluation metrics: area under the precision-sensitivity curve (AUPS) with a high sensitivity and AUPS with a high positive predictive value. The proposed phenotyping algorithms based on our framework show higher performance than baseline algorithms. Our proposed framework can be used to develop 2 types of phenotyping algorithms depending on the tuning approach: one for screening, the other for identifying research subjects. We develop a novel phenotyping framework that can be easily implemented on the basis of proper evaluation metrics, which are in accordance with users' objectives. The phenotyping algorithms based on our framework are useful for extraction of T2DM patients in retrospective studies.

Gene networks underlying convergent and pleiotropic phenotypes in a large and systematically-phenotyped cohort with heterogeneous developmental disorders.

PubMed

Andrews, Tallulah; Meader, Stephen; Vulto-van Silfhout, Anneke; Taylor, Avigail; Steinberg, Julia; Hehir-Kwa, Jayne; Pfundt, Rolph; de Leeuw, Nicole; de Vries, Bert B A; Webber, Caleb

2015-03-01

Readily-accessible and standardised capture of genotypic variation has revolutionised our understanding of the genetic contribution to disease. Unfortunately, the corresponding systematic capture of patient phenotypic variation needed to fully interpret the impact of genetic variation has lagged far behind. Exploiting deep and systematic phenotyping of a cohort of 197 patients presenting with heterogeneous developmental disorders and whose genomes harbour de novo CNVs, we systematically applied a range of commonly-used functional genomics approaches to identify the underlying molecular perturbations and their phenotypic impact. Grouping patients into 408 non-exclusive patient-phenotype groups, we identified a functional association amongst the genes disrupted in 209 (51%) groups. We find evidence for a significant number of molecular interactions amongst the association-contributing genes, including a single highly-interconnected network disrupted in 20% of patients with intellectual disability, and show using microcephaly how these molecular networks can be used as baits to identify additional members whose genes are variant in other patients with the same phenotype. Exploiting the systematic phenotyping of this cohort, we observe phenotypic concordance amongst patients whose variant genes contribute to the same functional association but note that (i) this relationship shows significant variation across the different approaches used to infer a commonly perturbed molecular pathway, and (ii) that the phenotypic similarities detected amongst patients who share the same inferred pathway perturbation result from these patients sharing many distinct phenotypes, rather than sharing a more specific phenotype, inferring that these pathways are best characterized by their pleiotropic effects.

Prognostic factors for chronic headache

PubMed Central

Bowers, Hannah; Caldwell, Fiona; Mistry, Dipesh; Underwood, Martin; Matharu, Manjit; Pincus, Tamar

2017-01-01

Objective: To identify predictors of prognosis and trial outcomes in prospective studies of people with chronic headache. Methods: This was a systematic review of published literature in peer-reviewed journals. We included (1) randomized controlled trials (RCTs) of interventions for chronic headache that reported subgroup analyses and (2) prospective cohort studies, published in English, since 1980. Participants included adults with chronic headache (including chronic headache, chronic migraine, and chronic tension-type headache with or without medication overuse headache). We searched key databases using free text and MeSH terms. Two reviewers independently extracted data and assessed the methodologic quality of studies and overall quality of evidence identified using appropriate published checklists. Results: We identified 16,556 titles, removed 663 duplicates, and reviewed 199 articles, of which 27 were included in the review—17 prospective cohorts and 10 RCTs with subgroup analyses reported. There was moderate-quality evidence indicating that depression, anxiety, poor sleep and stress, medication overuse, and poor self-efficacy for managing headaches are potential prognostic factors for poor prognosis and unfavorable outcomes from preventive treatment in chronic headache. There was inconclusive evidence about treatment expectations, age, age at onset, body mass index, employment, and several headache features. Conclusions: This review identified several potential predictors of poor prognosis and worse outcome postinterventions in people with chronic headache. The majority of these are modifiable. The findings also highlight the need for more longitudinal high-quality research of prognostic factors in chronic headache. PMID:28615422

Localized primary gastrointestinal diffuse large B cell lymphoma received a surgical approach: an analysis of prognostic factors and comparison of staging systems in 101 patients from a single institution.

PubMed

Zhang, Shengting; Wang, Li; Yu, Dong; Shen, Yang; Cheng, Shu; Zhang, Li; Qian, Ying; Shen, Zhixiang; Li, Qinyu; Zhao, Weili

2015-08-15

Diffuse large B cell lymphoma (DLBCL) represents the most common histological subtype of primary gastrointestinal lymphoma and is a heterogeneous group of disease. Prognostic characterization of individual patients is an essential prerequisite for a proper risk-based therapeutic choice. Clinical and pathological prognostic factors were identified, and predictive value of four previously described prognostic systems were assessed in 101 primary gastrointestinal DLBCL (PG-DLBCL) patients with localized disease, including Ann Arbor staging with Musshoff modification, International Prognostic Index (IPI), Lugano classification, and Paris staging system. Univariate factors correlated with inferior survival time were clinical parameters [age>60 years old, multiple extranodal/gastrointestinal involvement, elevated serum lactate dehydrogenase and β2-microglobulin, and decreased serum albumin], as well as pathological parameters (invasion depth beyond serosa, involvement of regional lymph node or adjacent tissue, Ki-67 index, and Bcl-2 expression). Major independent variables of adverse outcome indicated by multivariate analysis were multiple gastrointestinal involvement. In patients unfit for Rituximab but received surgery, radical surgery significantly prolonged the survival time, comparing with alleviative surgery. Addition of Rituximab could overcome the negative prognostic effect of alleviative surgery. Among the four prognostic systems, IPI and Lugano classification clearly separated patients into different risk groups. IPI was able to further stratify the early-stage patients of Lugano classification into groups with distinct prognosis. Radical surgery might be proposed for the patients unfit for Rituximab treatment, and a combination of clinical and pathological staging systems was more helpful to predict the disease outcome of PG-DLBCL patients.

Validation of cytogenetic risk groups according to International Prognostic Scoring Systems by peripheral blood CD34+FISH: results from a German diagnostic study in comparison with an international control group.

PubMed

Braulke, Friederike; Platzbecker, Uwe; Müller-Thomas, Catharina; Götze, Katharina; Germing, Ulrich; Brümmendorf, Tim H; Nolte, Florian; Hofmann, Wolf-Karsten; Giagounidis, Aristoteles A N; Lübbert, Michael; Greenberg, Peter L; Bennett, John M; Solé, Francesc; Mallo, Mar; Slovak, Marilyn L; Ohyashiki, Kazuma; Le Beau, Michelle M; Tüchler, Heinz; Pfeilstöcker, Michael; Nösslinger, Thomas; Hildebrandt, Barbara; Shirneshan, Katayoon; Aul, Carlo; Stauder, Reinhard; Sperr, Wolfgang R; Valent, Peter; Fonatsch, Christa; Trümper, Lorenz; Haase, Detlef; Schanz, Julie

2015-02-01

International Prognostic Scoring Systems are used to determine the individual risk profile of myelodysplastic syndrome patients. For the assessment of International Prognostic Scoring Systems, an adequate chromosome banding analysis of the bone marrow is essential. Cytogenetic information is not available for a substantial number of patients (5%-20%) with dry marrow or an insufficient number of metaphase cells. For these patients, a valid risk classification is impossible. In the study presented here, the International Prognostic Scoring Systems were validated based on fluorescence in situ hybridization analyses using extended probe panels applied to cluster of differentiation 34 positive (CD34(+)) peripheral blood cells of 328 MDS patients of our prospective multicenter German diagnostic study and compared to chromosome banding results of 2902 previously published patients with myelodysplastic syndromes. For cytogenetic risk classification by fluorescence in situ hybridization analyses of CD34(+) peripheral blood cells, the groups differed significantly for overall and leukemia-free survival by uni- and multivariate analyses without discrepancies between treated and untreated patients. Including cytogenetic data of fluorescence in situ hybridization analyses of peripheral CD34(+) blood cells (instead of bone marrow banding analysis) into the complete International Prognostic Scoring System assessment, the prognostic risk groups separated significantly for overall and leukemia-free survival. Our data show that a reliable stratification to the risk groups of the International Prognostic Scoring Systems is possible from peripheral blood in patients with missing chromosome banding analysis by using a comprehensive probe panel (clinicaltrials.gov identifier:01355913). Copyright© Ferrata Storti Foundation.

Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification.

PubMed

Andreiuolo, Felipe; Le Teuff, Gwénaël; Bayar, Mohamed Amine; Kilday, John-Paul; Pietsch, Torsten; von Bueren, André O; Witt, Hendrik; Korshunov, Andrey; Modena, Piergiorgio; Pfister, Stefan M; Pagès, Mélanie; Castel, David; Giangaspero, Felice; Chimelli, Leila; Varlet, Pascale; Rutkowski, Stefan; Frappaz, Didier; Massimino, Maura; Grundy, Richard; Grill, Jacques

2017-01-01

Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths. This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed. Among complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group. Integrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma.

Validation of the prognostic value of lymph node ratio in patients with cutaneous melanoma: a population-based study of 8,177 cases.

PubMed

Mocellin, Simone; Pasquali, Sandro; Rossi, Carlo Riccardo; Nitti, Donato

2011-07-01

The proportion of positive among examined lymph nodes (lymph node ratio [LNR]) has been recently proposed as an useful and easy-to-calculate prognostic factor for patients with cutaneous melanoma. However, its independence from the standard prognostic system TNM has not been formally proven in a large series of patients. Patients with histologically proven cutaneous melanoma were identified from the Surveillance Epidemiology End Results database. Disease-specific survival was the clinical outcome of interest. The prognostic ability of conventional factors and LNR was assessed by multivariable survival analysis using the Cox regression model. Eligible patients (n = 8,177) were diagnosed with melanoma between 1998 and 2006. Among lymph node-positive cases (n = 3,872), most LNR values ranged from 1% to 10% (n = 2,187). In the whole series (≥5 lymph nodes examined) LNR significantly contributed to the Cox model independently of the TNM effect on survival (hazard ratio, 1.28; 95% confidence interval, 1.23-1.32; P < .0001). On subgroup analysis, the significant and independent prognostic value of LNR was confirmed both in patients with ≥10 lymph nodes examined (n = 4,381) and in those with TNM stage III disease (n = 3,658). In all cases, LNR increased the prognostic accuracy of the survival model. In this large series of patients, the LNR independently predicted disease-specific survival, improving the prognostic accuracy of the TNM system. Accordingly, the LNR should be taken into account for the stratification of patients' risk, both in clinical and research settings. Copyright © 2011 Mosby, Inc. All rights reserved.

Nonsentinel lymph node status in patients with cutaneous melanoma: results from a multi-institution prognostic study.

PubMed

Pasquali, Sandro; Mocellin, Simone; Mozzillo, Nicola; Maurichi, Andrea; Quaglino, Pietro; Borgognoni, Lorenzo; Solari, Nicola; Piazzalunga, Dario; Mascheroni, Luigi; Giudice, Giuseppe; Patuzzo, Roberto; Caracò, Corrado; Ribero, Simone; Marone, Ugo; Santinami, Mario; Rossi, Carlo Riccardo

2014-03-20

We investigated whether the nonsentinel lymph node (NSLN) status in patients with melanoma improves the prognostic accuracy of common staging features; then we formulated a proposal for including the NSLN status in the current melanoma staging system. We retrospectively collected the clinicopathologic data of 1,538 patients with positive SLN status who underwent completion lymph node dissection (CLND) at nine Italian centers. Multivariable Cox regression survival analysis was used to identify independent prognostic factors. Literature meta-analysis was used to summarize the available evidence on the prognostic value of the NSLN status in patients with positive SLN. NSLN metastasis was observed in 353 patients (23%). After a median follow-up of 45 months, NSLN status was an independent prognostic factor for melanoma-specific survival (hazard ratio [HR] = 1.34; 95% CI, 1.18 to 1.52; P < .001). NSLN status efficiently stratified the prognosis of patients with two to three positive lymph nodes (n = 387; HR = 1.39; 95% CI, 1.07 to 1.81; P = .013), independently of other staging features. Searching the literature, this patient subgroup was investigated in other two studies. Pooling the results (n = 620 patients; 284 NSLN negative and 336 NSLN positive), we found that NSLN status is a highly significant prognostic factor (summary HR = 1.59; 95% CI, 1.27 to 1.98; P < .001) in patients with two to three positive lymph nodes. These findings support the independent prognostic value of the NSLN status in patients with two to three positive lymph nodes, suggesting that this information should be considered for the routine staging in patients with melanoma.

Molecular Classification Substitutes for the Prognostic Variables Stage, Age, and MYCN Status in Neuroblastoma Risk Assessment.

PubMed

Rosswog, Carolina; Schmidt, Rene; Oberthuer, André; Juraeva, Dilafruz; Brors, Benedikt; Engesser, Anne; Kahlert, Yvonne; Volland, Ruth; Bartenhagen, Christoph; Simon, Thorsten; Berthold, Frank; Hero, Barbara; Faldum, Andreas; Fischer, Matthias

2017-12-01

Current risk stratification systems for neuroblastoma patients consider clinical, histopathological, and genetic variables, and additional prognostic markers have been proposed in recent years. We here sought to select highly informative covariates in a multistep strategy based on consecutive Cox regression models, resulting in a risk score that integrates hazard ratios of prognostic variables. A cohort of 695 neuroblastoma patients was divided into a discovery set (n=75) for multigene predictor generation, a training set (n=411) for risk score development, and a validation set (n=209). Relevant prognostic variables were identified by stepwise multivariable L1-penalized least absolute shrinkage and selection operator (LASSO) Cox regression, followed by backward selection in multivariable Cox regression, and then integrated into a novel risk score. The variables stage, age, MYCN status, and two multigene predictors, NB-th24 and NB-th44, were selected as independent prognostic markers by LASSO Cox regression analysis. Following backward selection, only the multigene predictors were retained in the final model. Integration of these classifiers in a risk scoring system distinguished three patient subgroups that differed substantially in their outcome. The scoring system discriminated patients with diverging outcome in the validation cohort (5-year event-free survival, 84.9±3.4 vs 63.6±14.5 vs 31.0±5.4; P<.001), and its prognostic value was validated by multivariable analysis. We here propose a translational strategy for developing risk assessment systems based on hazard ratios of relevant prognostic variables. Our final neuroblastoma risk score comprised two multigene predictors only, supporting the notion that molecular properties of the tumor cells strongly impact clinical courses of neuroblastoma patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Identification of novel cytogenetic markers with prognostic significance in a series of 968 patients with primary myelodysplastic syndromes.

PubMed

Solé, Francesc; Luño, Elisa; Sanzo, Carmen; Espinet, Blanca; Sanz, Guillermo F; Cervera, José; Calasanz, María José; Cigudosa, Juan Cruz; Millà, Fuensanta; Ribera, Josep Maria; Bureo, Encarna; Marquez, Maria Luisa; Arranz, Eva; Florensa, Lourdes

2005-09-01

The main prognostic factors in myelodysplastic syndromes (MDS) are chromosomal abnormalities, the proportion of blasts in bone marrow and number and degree of cytopenias. A consensus-defined International Prognostic Scoring System (IPSS) for predicting outcome and planning therapy in MDS has been developed, but its prognostic value in a large and independent series remains unproven. Furthermore, the intermediate-risk cytogenetic subgroup defined by the IPSS includes a miscellaneous number of different single abnormalities of uncertain prognostic significance at present. The main aim of the present study was to identify chromosomal abnormalities with a previously unrecognized good or poor prognosis in order to find new cytogenetic markers with predictive value. We report the cytogenetic findings in a series of 968 patients with primary MDS from the Spanish Cytogenetics Working Group, Grupo Cooperativo Español de Citogenética Hematológica (GCECGH). In this series of 968 MDS patients, we found various cytogenetic aberrations with a new prognostic impact. Complex karyotype, -7/7q- and i(17q) had a poor prognosis; normal karyotype, loss of Y chromosome, deletion 11q, deletion 12p and deletion 20q as single alterations had a good prognosis. Intermediate prognosis aberrations were rearrangements of 3q21q26, trisomy 8, trisomy 9, translocations of 11q and del(17p). Finally, a new group of single or double cytogenetic abnormalities, most of which are considered rare cytogenetic events and are usually included in the intermediate category of the IPSS, showed a trend to poor prognosis. This study suggests that some specific chromosomal abnormalities could be segregated from the IPSS intermediate-risk cytogenetic prognostic subgroup and included in the low risk or in the poor risk groups.

ExSurv: A Web Resource for Prognostic Analyses of Exons Across Human Cancers Using Clinical Transcriptomes

PubMed Central

Hashemikhabir, Seyedsasan; Budak, Gungor; Janga, Sarath Chandra

2016-01-01

Survival analysis in biomedical sciences is generally performed by correlating the levels of cellular components with patients’ clinical features as a common practice in prognostic biomarker discovery. While the common and primary focus of such analysis in cancer genomics so far has been to identify the potential prognostic genes, alternative splicing – a posttranscriptional regulatory mechanism that affects the functional form of a protein due to inclusion or exclusion of individual exons giving rise to alternative protein products, has increasingly gained attention due to the prevalence of splicing aberrations in cancer transcriptomes. Hence, uncovering the potential prognostic exons can not only help in rationally designing exon-specific therapeutics but also increase specificity toward more personalized treatment options. To address this gap and to provide a platform for rational identification of prognostic exons from cancer transcriptomes, we developed ExSurv (https://exsurv.soic.iupui.edu), a web-based platform for predicting the survival contribution of all annotated exons in the human genome using RNA sequencing-based expression profiles for cancer samples from four cancer types available from The Cancer Genome Atlas. ExSurv enables users to search for a gene of interest and shows survival probabilities for all the exons associated with a gene and found to be significant at the chosen threshold. ExSurv also includes raw expression values across the cancer cohort as well as the survival plots for prognostic exons. Our analysis of the resulting prognostic exons across four cancer types revealed that most of the survival-associated exons are unique to a cancer type with few processes such as cell adhesion, carboxylic, fatty acid metabolism, and regulation of T-cell signaling common across cancer types, possibly suggesting significant differences in the posttranscriptional regulatory pathways contributing to prognosis. PMID:27528797

Radiogenomics of hepatocellular carcinoma: multiregion analysis-based identification of prognostic imaging biomarkers by integrating gene data—a preliminary study

NASA Astrophysics Data System (ADS)

Xia, Wei; Chen, Ying; Zhang, Rui; Yan, Zhuangzhi; Zhou, Xiaobo; Zhang, Bo; Gao, Xin

2018-02-01

Our objective was to identify prognostic imaging biomarkers for hepatocellular carcinoma in contrast-enhanced computed tomography (CECT) with biological interpretations by associating imaging features and gene modules. We retrospectively analyzed 371 patients who had gene expression profiles. For the 38 patients with CECT imaging data, automatic intra-tumor partitioning was performed, resulting in three spatially distinct subregions. We extracted a total of 37 quantitative imaging features describing intensity, geometry, and texture from each subregion. Imaging features were selected after robustness and redundancy analysis. Gene modules acquired from clustering were chosen for their prognostic significance. By constructing an association map between imaging features and gene modules with Spearman rank correlations, the imaging features that significantly correlated with gene modules were obtained. These features were evaluated with Cox’s proportional hazard models and Kaplan-Meier estimates to determine their prognostic capabilities for overall survival (OS). Eight imaging features were significantly correlated with prognostic gene modules, and two of them were associated with OS. Among these, the geometry feature volume fraction of the subregion, which was significantly correlated with all prognostic gene modules representing cancer-related interpretation, was predictive of OS (Cox p  =  0.022, hazard ratio  =  0.24). The texture feature cluster prominence in the subregion, which was correlated with the prognostic gene module representing lipid metabolism and complement activation, also had the ability to predict OS (Cox p  =  0.021, hazard ratio  =  0.17). Imaging features depicting the volume fraction and textural heterogeneity in subregions have the potential to be predictors of OS with interpretable biological meaning.

Number of negative lymph nodes should be considered for incorporation into staging for breast cancer

PubMed Central

Wu, San-Gang; Wang, Yan; Zhou, Juan; Sun, Jia-Yuan; Li, Feng-Yan; Lin, Huan-Xin; He, Zhen-Yu

2015-01-01

This study aimed to investigate the prognostic value of the number of involved lymph nodes (pN), number of removed lymph nodes (RLNs), lymph node ratio (LNR), number of negative lymph nodes (NLNs), and log odds of positive lymph nodes (LODDS) in breast cancer patients. The records of 2,515 breast cancer patients who received a mastectomy or breast-conserving surgery were retrospectively reviewed. The log-rank test was used to compare survival curves, and Cox regression analysis was performed to identify prognostic factors. The median follow-up time was 64.2 months, and the 8-year disease-free survival (DFS) and overall survival (OS) were 74.6% and 82.3%, respectively. Univariate analysis showed that pN stage, LNR, number of RLNs, and number of NLNs were significant prognostic factors for DFS and OS (all, P < 0.05). LODDS was a significant prognostic factor for OS (P = 0.021). Multivariate analysis indicated that pN stage and the number of NLNs were independent prognostic factors for DFS and OS. A higher number of NLNs was associated with higher DFS and OS, and a higher number of involved lymph nodes were associated with poorer DFS and OS. Patients with a NLNs count > 9 had better survival (P < 0.001). Subgroup analysis showed that the NLNs count had a prognostic value in patients with different pT stages and different lymph node status (log-rank P < 0.05). For breast cancer, pN stage and NLNs count have a better prognostic value compared to the RLNs count, LNR, and LODDS. Number of negative lymph nodes should be considered for incorporation into staging for breast cancer. PMID:25973321

Prognostic value of cardiovascular magnetic resonance imaging measurements corrected for age and sex in idiopathic pulmonary arterial hypertension.

PubMed

Swift, Andrew J; Rajaram, Smitha; Campbell, Michael J; Hurdman, Judith; Thomas, Steve; Capener, Dave; Elliot, Charlie; Condliffe, Robin; Wild, Jim M; Kiely, David G

2014-01-01

There are limited data on the prognostic value of cardiovascular magnetic resonance measurements in idiopathic pulmonary arterial hypertension, with no studies investigating the impact of correction of cardiovascular magnetic resonance indices for age and sex on prognostic value. Consecutive patients with idiopathic pulmonary arterial hypertension underwent cardiovascular magnetic resonance imaging at 1.5T. Steady-state free precession cardiac volumes and mass measurements were corrected for age, sex, and body surface area according to reference data and prognostic significance assessed. A total of 80 patients with idiopathic pulmonary arterial hypertension were identified, and 23 patients died during the mean follow-up of 32±14 months. Corrected for age, sex, and body surface area, right ventricular end-systolic volume (P=0.004) strongly predicted mortality, independent of World Health Organization functional class, mean right atrial pressure, cardiac index, and mixed venous oxygen saturations. Consideration should be given to correcting cardiovascular magnetic resonance measures for age, sex, and body surface area, particularly given the changing demographics of patients with idiopathic pulmonary arterial hypertension. Corrected right ventricular end-systolic volume is a strong prognostic marker in idiopathic pulmonary arterial hypertension, independent of invasively derived measurements, mean right atrial pressure cardiac index, and mixed venous oxygen saturations.

Big genomics and clinical data analytics strategies for precision cancer prognosis.

PubMed

Ow, Ghim Siong; Kuznetsov, Vladimir A

2016-11-07

The field of personalized and precise medicine in the era of big data analytics is growing rapidly. Previously, we proposed our model of patient classification termed Prognostic Signature Vector Matching (PSVM) and identified a 37 variable signature comprising 36 let-7b associated prognostic significant mRNAs and the age risk factor that stratified large high-grade serous ovarian cancer patient cohorts into three survival-significant risk groups. Here, we investigated the predictive performance of PSVM via optimization of the prognostic variable weights, which represent the relative importance of one prognostic variable over the others. In addition, we compared several multivariate prognostic models based on PSVM with classical machine learning techniques such as K-nearest-neighbor, support vector machine, random forest, neural networks and logistic regression. Our results revealed that negative log-rank p-values provides more robust weight values as opposed to the use of other quantities such as hazard ratios, fold change, or a combination of those factors. PSVM, together with the classical machine learning classifiers were combined in an ensemble (multi-test) voting system, which collectively provides a more precise and reproducible patient stratification. The use of the multi-test system approach, rather than the search for the ideal classification/prediction method, might help to address limitations of the individual classification algorithm in specific situation.

Percutaneous Endoscopic Gastrostomy Tube Is a Negative Prognostic Factor for Recurrent/Metastatic Head and Neck Cancer.

PubMed

Siano, Marco; Jarisch, Nadine; Joerger, Markus; Espeli, Vittoria

2018-06-01

Recurrent/metastatic head and neck squamous cell cancer (r/mHNSCC) patients often need a percutaneous endoscopic gastrostomy feeding tube (PEG). Among known prognostic factors, PEG could be prognostic as well. We retrospectively analyzed r/mHNSCC patients referred for systemic treatment. Kaplan-Meier and multivariate cox regression models were applied to assess prognostic impact of PEG. One hunderd and ten patients were identified, 42 had a PEG at treatment start. Median survival from start of 1st-line systemic treatment was 8 months (95%CI=6.5-12.0 months), 4.5 months (95%CI=2.5-7.0 months) for patients with PEG and 11.5 months (95%CI=7.5-14.5 months) without PEG (adjusted HR=1.98, p=0.011). Similarly, survival from first recurrence of distant metastases was lower in patients with PEG as compared to patients without (7.5 vs. 15.5 months, adjusted HR=2.60, p<0.001). Presence of PEG feeding tube has an unfavourable prognostic impact on survival in patients with r/mHNSCC. While any causality remains speculative, potential complications should be appreciated before PEG implantation. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Multi-system Component Phenotypes of Bipolar Disorder for Genetic Investigations of Extended Pedigrees

PubMed Central

Fears, Scott C.; Service, Susan K.; Kremeyer, Barbara; Araya, Carmen; Araya, Xinia; Bejarano, Julio; Ramirez, Margarita; Castrillón, Gabriel; Gomez-Franco, Juliana; Lopez, Maria C.; Montoya, Gabriel; Montoya, Patricia; Aldana, Ileana; Teshiba, Terri M.; Abaryan, Zvart; Al-Sharif, Noor B.; Ericson, Marissa; Jalbrzikowski, Maria; Luykx, Jurjen J.; Navarro, Linda; Tishler, Todd A.; Altshuler, Lori; Bartzokis, George; Escobar, Javier; Glahn, David C.; Ospina-Duque, Jorge; Risch, Neil; Ruiz-Linares, Andrés; Thompson, Paul M.; Cantor, Rita M.; Lopez-Jaramillo, Carlos; Macaya, Gabriel; Molina, Julio; Reus, Victor I.; Sabatti, Chiara; Freimer, Nelson B.; Bearden, Carrie E.

2014-01-01

IMPORTANCE Genetic factors contribute to risk for bipolar disorder (BP), yet its pathogenesis remains poorly understood. A focus on measuring multi-system quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that impact on BP as well as its component phenotypes. OBJECTIVE To identify quantitative neurocognitive, temperament-related, and neuroanatomic phenotypes that appear heritable and associated with severe bipolar disorder (BP-I), and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN Multi-generational pedigree study in two closely related, genetically isolated populations: the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (ANT). PARTICIPANTS 738 individuals, all from CVCR and ANT pedigrees, of whom 181 are affected with BP-I. MAIN OUTCOME MEASURE Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) phenotypes. RESULTS Seventy-five percent (126) of the phenotypes investigated were significantly heritable, and 31% (53) were associated with BP-I. About 1/4 of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions, and volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND RELEVANCE This is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I-association within families that is consistent with expectations from case-control studies. Together these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder. PMID:24522887

The relationship of transversus abdominis and lumbar multifidus activation and prognostic factors for clinical success with a stabilization exercise program: a cross-sectional study.

PubMed

Hebert, Jeffrey J; Koppenhaver, Shane L; Magel, John S; Fritz, Julie M

2010-01-01

Hebert JJ, Koppenhaver SL, Magel JS, Fritz JM. The relationship of transversus abdominis and lumbar multifidus activation and prognostic factors for clinical success with a stabilization exercise program: a cross-sectional study. To examine the relationship between prognostic factors for clinical success with a stabilization exercise program and lumbar multifidus (LM) and transversus abdominis (TrA) muscle activation assessed using rehabilitative ultrasound imaging (RUSI). Cross-sectional study. Outpatient physical therapy clinic. Volunteers with current low back pain (N=40). Not applicable. We examined the relationship between prognostic factors associated with clinical success with a stabilization exercise program (positive prone instability test, age <40y, aberrant movements, straight leg raise >91 degrees , presence of lumbar hypermobility) and degree of TrA and LM muscle activation assessed by RUSI. Significant univariate relationships were identified between LM muscle activation and the number of prognostic factors present (Pearson correlation coefficient [r] =-.558, P=.001), as well as the individual factors of a positive prone instability test (point biserial correlation coefficient [r(pbis)]=.376, P=.018) and segmental hypermobility (r(pbis)=.358, P=.025). The multivariate analyses indicated that after controlling for other variables, the addition of the variable "number of prognostic factors present" resulted in a significant increase in R(2) (P=.006). No significant univariate or multivariate relationships were observed between the prognostic factors and TrA muscle activation. Decreased LM muscle activation, but not TrA muscle activation, is associated with the presence of factors predictive of clinical success with a stabilization exercise program. Our findings provide researchers and clinicians with evidence regarding the construct validity of the prognostic factors examined in this study, as well as the potential clinical importance of the LM muscle as a target for stabilization exercises. Copyright (c) 2010 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Prognostic Prediction Model for Second Allogeneic Stem-Cell Transplantation in Patients With Relapsed Acute Myeloid Leukemia: Single-Center Report.

PubMed

Park, Sung-Soo; Kim, Hee-Je; Min, Kyoung Il; Min, Gi June; Jeon, Young-Woo; Yoon, Jae-Ho; Yahng, Seung-Ah; Shin, Seung-Hwan; Lee, Sung-Eun; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Lee, Seok; Min, Chang-Ki; Cho, Seok-Goo; Kim, Dong-Wook; Lee, Jong Wook; Min, Woo-Sung

2018-04-01

To identify factors affecting survival outcomes and to develop a prognostic model for second allogeneic stem-cell transplantation (allo-SCT2) for relapsed acute myeloid leukemia (AML) after the first autologous or allogeneic stem-cell transplantation. Seventy-eight consecutive adult AML patients who received allo-SCT2 were analyzed in this retrospective study. The 4-year overall survival (OS) rate was 28.7%. In multivariate analysis, poor cytogenetic risk at diagnosis, circulating blast ≥ 20% at relapse, duration from first transplantation to relapse < 9 months, and failure to achieve morphologic complete remission after allo-SCT2 were factors associated with poor OS. A prognostic model was developed with the following score system: intermediate and poor cytogenetic risk at diagnosis (0.5 and 1 point), peripheral blast ≥ 20% at relapse (1 point), duration from the first transplantation to relapse < 9 months (1 point), and failure to achieve morphologic complete remission after allo-SCT2 (1 point). The model identified 2 subgroups according to the 4-year OS rate: 51.3% in the low-risk group (score < 2) and 2.8% in the high-risk group (score ≥ 2) (P < .001). This prognostic model might be useful to make an appropriate decision for allo-SCT2 in relapsed AML after the first autologous or allogeneic stem-cell transplantation. Copyright © 2018 Elsevier Inc. All rights reserved.

Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation.

PubMed

Fenske, Timothy S; Ahn, Kwang W; Graff, Tara M; DiGilio, Alyssa; Bashir, Qaiser; Kamble, Rammurti T; Ayala, Ernesto; Bacher, Ulrike; Brammer, Jonathan E; Cairo, Mitchell; Chen, Andy; Chen, Yi-Bin; Chhabra, Saurabh; D'Souza, Anita; Farooq, Umar; Freytes, Cesar; Ganguly, Siddhartha; Hertzberg, Mark; Inwards, David; Jaglowski, Samantha; Kharfan-Dabaja, Mohamed A; Lazarus, Hillard M; Nathan, Sunita; Pawarode, Attaphol; Perales, Miguel-Angel; Reddy, Nishitha; Seo, Sachiko; Sureda, Anna; Smith, Sonali M; Hamadani, Mehdi

2016-07-01

For diffuse large B-cell lymphoma (DLBCL) patients progressing after autologous haematopoietic cell transplantation (autoHCT), allogeneic HCT (alloHCT) is often considered, although limited information is available to guide patient selection. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 503 patients who underwent alloHCT after disease progression/relapse following a prior autoHCT. The 3-year probabilities of non-relapse mortality, progression/relapse, progression-free survival (PFS) and overall survival (OS) were 30, 38, 31 and 37% respectively. Factors associated with inferior PFS on multivariate analysis included Karnofsky performance status (KPS) <80, chemoresistance, autoHCT to alloHCT interval <1-year and myeloablative conditioning. Factors associated with worse OS on multivariate analysis included KPS<80, chemoresistance and myeloablative conditioning. Three adverse prognostic factors were used to construct a prognostic model for PFS, including KPS<80 (4 points), autoHCT to alloHCT interval <1-year (2 points) and chemoresistant disease at alloHCT (5 points). This CIBMTR prognostic model classified patients into four groups: low-risk (0 points), intermediate-risk (2-5 points), high-risk (6-9 points) or very high-risk (11 points), predicting 3-year PFS of 40, 32, 11 and 6%, respectively, with 3-year OS probabilities of 43, 39, 19 and 11% respectively. In conclusion, the CIBMTR prognostic model identifies a subgroup of DLBCL patients experiencing long-term survival with alloHCT after a failed prior autoHCT. © 2016 John Wiley & Sons Ltd.

Association of immunophenotypic characterization of peripheral lymphocytes with different clinical phenotypes of tuberculosis in Chinese Han children.

PubMed

Xiao, Jing; Sun, Lin; Wu, Xi-Rong; Miao, Qing; Jiao, Wei-Wei; Shen, Chen; Shen, Dan; Feng, Wei-Xing; Liu, Fang; Shen, A-Dong

2012-01-01

Very few researchers have studied the changes in peripheral lymphocyte patterns in adult tuberculosis (TB) and even less researches have been conducted in pediatric TB. In this study, we obtained blood samples from 114 Chinese pediatric TB patients and 116 matched controls to study the association of phenotypic subsets of peripheral lymphocytes with different clinical phenotypes of TB. The subjects were classified as the control group and the TB patients group which were further divided into a pulmonary TB group and an extra-pulmonary TB group (more serious than the former). The distribution of lymphocyte subpopulations, including T lymphocytes, CD4(+) T lymphocytes, CD8(+) T lymphocytes, B lymphocytes, and natural killer (NK) cells, were quantitatively analyzed by flow cytometry. Compared to the healthy controls, TB infection was associated with significantly higher B cell (P < 0.0001), and lower T cell (P = 0.029) and NK cell (P < 0.0001) percentages. Compared to pulmonary TB patients, extra-pulmonary TB was associated with relatively higher B cell (P = 0.073), and lower T cell percentages (P = 0.021), higher purified protein derivative (PPD) negative rate (P = 0.061), and poorer PPD response (P = 0.010). Most pulmonary TB cases were primary pulmonary TB (89.1%), and most extra-pulmonary TB cases had TB meningitis (72.1%). This study demonstrates changes in the lymhocyte distribution in children suffering from different clinical phenotypes of TB; such as primary pulmonary TB, and TB meningitis. These patterns may have significance in understanding the pathogenesis and prognostic markers of the disease, and for developing immunomodulatory modalities of therapy.

Comparison of clinical outcome after autologous stem cell transplantation between patients with peripheral T-cell lymphomas and diffuse large B-cell lymphoma.

PubMed

Sohn, B S; Park, I; Kim, E K; Yoon, D H; Lee, S S; Kang, B W; Jang, G; Choi, Y H; Kim, C; Lee, D H; Kim, S; Huh, J; Suh, C

2009-09-01

Although patients with T-cell phenotype lymphomas are generally accepted to have worse prognosis than B-cell phenotype lymphomas, the studies comparing outcomes after autologous stem cell transplantation (ASCT) between peripheral T-cell lymphomas (PTCLs) and with diffuse large B-cell lymphoma (DLBCL) are few. In this study, we compared outcomes after ASCT between 23 patients with PTCLs and 54 patients with DLBCL. Univariate analysis showed that the timing of ASCT, complete response (CR) at ASCT, favorable lactate dehydrogenase/performance/stage, low/low-intermediate (L-LI) International Prognostic Index (IPI) and L-LI age-adjusted IPI (aaIPI) at ASCT were significant predictors of both OS and EFS. Multivariate analysis showed that CR and L-LI aaIPI at ASCT were favorable for both OS (hazard ratio (HR), 0.34; 95% CI, 0.14-0.81; P=0.016 and HR, 0.27; 95% CI, 0.12-0.57; P=0.001) and EFS (HR, 0.38; 95% CI, 0.17-0.85; P=0.020 and HR, 0.36; 95% CI, 0.17-0.77; P=0.008). B-cell or T-cell phenotype, however, had no impact on OS (HR, 0.56; 95% CI, 0.27-1.18; P=0.126) or EFS (HR, 0.62; 95% CI, 0.30-1.30; P=0.206). In conclusion, when compared to patients with DLBCL, patients with PTCLs did not have inferior outcomes after ASCT. T-cell phenotype itself may not have an effect on outcomes of PTCL patients who underwent ASCT.

Latent class analysis derived subgroups of low back pain patients - do they have prognostic capacity?

PubMed

Molgaard Nielsen, Anne; Hestbaek, Lise; Vach, Werner; Kent, Peter; Kongsted, Alice

2017-08-09

Heterogeneity in patients with low back pain is well recognised and different approaches to subgrouping have been proposed. One statistical technique that is increasingly being used is Latent Class Analysis as it performs subgrouping based on pattern recognition with high accuracy. Previously, we developed two novel suggestions for subgrouping patients with low back pain based on Latent Class Analysis of patient baseline characteristics (patient history and physical examination), which resulted in 7 subgroups when using a single-stage analysis, and 9 subgroups when using a two-stage approach. However, their prognostic capacity was unexplored. This study (i) determined whether the subgrouping approaches were associated with the future outcomes of pain intensity, pain frequency and disability, (ii) assessed whether one of these two approaches was more strongly or more consistently associated with these outcomes, and (iii) assessed the performance of the novel subgroupings as compared to the following variables: two existing subgrouping tools (STarT Back Tool and Quebec Task Force classification), four baseline characteristics and a group of previously identified domain-specific patient categorisations (collectively, the 'comparator variables'). This was a longitudinal cohort study of 928 patients consulting for low back pain in primary care. The associations between each subgroup approach and outcomes at 2 weeks, 3 and 12 months, and with weekly SMS responses were tested in linear regression models, and their prognostic capacity (variance explained) was compared to that of the comparator variables listed above. The two previously identified subgroupings were similarly associated with all outcomes. The prognostic capacity of both subgroupings was better than that of the comparator variables, except for participants' recovery beliefs and the domain-specific categorisations, but was still limited. The explained variance ranged from 4.3%-6.9% for pain intensity and from 6.8%-20.3% for disability, and highest at the 2 weeks follow-up. Latent Class-derived subgroups provided additional prognostic information when compared to a range of variables, but the improvements were not substantial enough to warrant further development into a new prognostic tool. Further research could investigate if these novel subgrouping approaches may help to improve existing tools that subgroup low back pain patients.

Large-scale external validation and comparison of prognostic models: an application to chronic obstructive pulmonary disease.

PubMed

Guerra, Beniamino; Haile, Sarah R; Lamprecht, Bernd; Ramírez, Ana S; Martinez-Camblor, Pablo; Kaiser, Bernhard; Alfageme, Inmaculada; Almagro, Pere; Casanova, Ciro; Esteban-González, Cristóbal; Soler-Cataluña, Juan J; de-Torres, Juan P; Miravitlles, Marc; Celli, Bartolome R; Marin, Jose M; Ter Riet, Gerben; Sobradillo, Patricia; Lange, Peter; Garcia-Aymerich, Judith; Antó, Josep M; Turner, Alice M; Han, Meilan K; Langhammer, Arnulf; Leivseth, Linda; Bakke, Per; Johannessen, Ane; Oga, Toru; Cosio, Borja; Ancochea-Bermúdez, Julio; Echazarreta, Andres; Roche, Nicolas; Burgel, Pierre-Régis; Sin, Don D; Soriano, Joan B; Puhan, Milo A

2018-03-02

External validations and comparisons of prognostic models or scores are a prerequisite for their use in routine clinical care but are lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD. We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment consortium, corresponding to primary, secondary, and tertiary care in Europe, the Americas, and Japan. These studies include globally 15,762 patients with COPD (1871 deaths and 42,203 person years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity, and inconsistency and provided a performance ranking of the prognostic scores. Depending on data availability, between two and nine prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea, and exercise capacity) had a median area under the curve (AUC) of 0.679 [1st quartile-3rd quartile = 0.655-0.733] across cohorts. The ADO score (age, dyspnea, and airflow obstruction) showed the best performance for predicting mortality (difference AUC ADO - AUC BODE = 0.015 [95% confidence interval (CI) = -0.002 to 0.032]; p = 0.08) followed by the updated BODE (AUC BODE updated - AUC BODE = 0.008 [95% CI = -0.005 to +0.022]; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small, and we did not identify any local or global inconsistency. Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any medical field to identify the best scores, possibly paving the way for stratified medicine, public health, and research.