Ben Davidson

Oslo University Hospital, Kristiania (historical), Oslo, Norway

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Publications (356)

  • Elisabeth Smogeli · Ben Davidson · Milada Cvancarova · [...] · Kristina Lindemann
    [Show abstract] [Hide abstract] ABSTRACT: Background L1 cell adhesion molecule (L1CAM) overexpression has been reported to be strongly associated with poor prognosis in early stage endometrial cancer (EC). We aimed at the validation of L1CAM as a marker of poor prognosis in an independent study population. Methods Patients with endometrioid EC FIGO stage I, were treated at Oslo University Hospital between 2005 and 2012. L1CAM expression was detected by immunohistochemistry with >10 % L1CAM staining defined as positive. Risks of relapse and death were estimated as hazard ratios (HRs) with 95 % confidence intervals (95 % CI). Results Of 450 patients, 388 (86 %) were evaluable for L1CAM expression and 35 (9 %) were L1CAM positive. After follow-up for a median time of 4.8 years (0.1–8.8), 33 (8 %) patients had recurred. 6/35 (17 %) L1CAM positive patients relapsed compared to 27/353 (8 %) L1CAM-negative patients. There were 7 (20 %) deaths in the L1CAM positive group, and 34 (10 %) in the negative group. In multivariate analysis, controlled for age and FIGO stage, L1CAM positivity was not significantly associated with the risk of relapse (HR 2.08, 95 % CI: 0.85–5.10, p = 0.11) or death of all-cause (HR 1.81, 95 % CI: 0.79–4.11, p = 0.16). In patients who were not treated with chemotherapy, L1CAM was significantly associated with risk of relapse (HR 2.9; 95 % CI: 1.08–7.56; p = 0.04). Conclusion Our report confirms that L1CAM is associated with a more aggressive tumortype and more distant relapses. The overall recurrence rate in this population was low as were the absolute differences between L1CAM positive and negative patients. In this independent study sample, L1CAM failed to be a clinically relevant marker of poor prognosis in stage I endometrioid endometrial carcinoma.
    Article · Dec 2016 · BMC Cancer
  • Ben Davidson
    [Show abstract] [Hide abstract] ABSTRACT: With the exception of hematological malignancies, flow cytometry (FC) is infrequently applied as an ancillary tool in the diagnosis of malignant effusions in most institutions. However, FC may be effectively used to differentiate between epithelial cells, mesothelial cells and leukocytes using antibodies against both cell surface and intracellular proteins, offering the advantage of quantitative analysis. Additionally, FC may be applied to the quantitative detection of cancer-associated molecules, including stem cell markers, as well as assessment of critical cellular processes, such as proliferation and apoptosis. Some of the latter tests may have relevance for monitoring treatment response in the presence of metastatic disease, although this does not constitute routine practice to date. This review summarizes current knowledge regarding the application of FC to serous effusions in the diagnostic setting, as well as in research into cancer biology focusing on clinical specimens. The studies published to date suggest a role for this method in the clinical setting in the context of diagnosis, prediction and prognosis.
    Article · Aug 2016 · Acta cytologica
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    Antonio Agostini · Ioannis Panagopoulos · Ben Davidson · [...] · Francesca Micci
    [Show abstract] [Hide abstract] ABSTRACT: Neoplasms of the ovary are the second most common tumor of the female reproductive system, and the most lethal of the gynecological malignancies. Ovarian tumors are divided into a copious number of different groups reflecting their different features. The present study analyzed 187 ovarian tumors (39 sex‑cord stromal tumors, 22 borderline tumors and 126 carcinomas) for the expression of the high‑mobility group AT‑hook 2 (HMGA2) gene, for mutations in the isocitrate dehydrogenase (NADP(+)) 1, cytosolic (IDH1), isocitrate dehydrogenase (NADP(+)) 2, mitochondrial (IDH2) and telomerase reverse transcriptase (TERT) genes, and for methylation of the O6‑methylguanine‑DNA methyltransferase (MGMT) promoter. Reverse transcription‑polymerase chain reaction analysis showed that HMGA2 was expressed in 74.5% of the samples (120/161). A truncated transcript of HMGA2 was identified in 11 cases. A novel truncated form of HMGA2 was found in 4 serous high‑grade carcinomas. Only 4 tumors (4/185) showed the TERT C228T mutation. No IDH1 or IDH2 mutations were found. Methylation of the promoter of MGMT was found in 2 borderline tumors (2/185). HMGA2 was expressed, in its truncated and native form, in different ovarian tumors, even the less aggressive types, underscoring the general importance of this gene in ovarian tumorigenesis. Mutations involving TERT, as well as MGMT promoter methylation, are rare events in ovarian tumors.
    Full-text Article · Jun 2016 · Oncology letters
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    [Show abstract] [Hide abstract] ABSTRACT: Recent cytogenetic and molecular investigations have improved our understanding of endometrial stromal tumors, including sarcomas (ESS), and helped redefine their classification into more pathogenetically meaningful categories. Since much more can be gained through such studies, we add information on another 22 ESS examined by karyotyping, PCR analysis, expression array analysis, and transcriptome sequencing. In spite of the known preference for certain pathogenetic pathways, we found considerable genetic heterogeneity in high-grade (HG) as well as in low-grade (LG) ESS. Not all HG tumors showed a YWHAE-NUTM chimeric transcript and as many as six LGESS showed no hitherto known ESS-related fusions. Among the transcripts identified by transcriptome sequencing and verified by Sanger sequencing, new variants of ZC3H7-BCOR and its reciprocal BCOR-ZC3H7 were identified as was involvement of the CREBBP and MLLT4 genes (both well known leukemia-related genes) in two new fusions. FISH analysis identified a known EPC1-PHF1 fusion which led to the identification of a new variant at the molecular level. The fact that around 70 genes were found differentially expressed, by microarray analysis, when comparing LGESS showing ESS-related fusions with LGESS without such transcripts, underscores the biochemical importance of the observed genetic heterogeneity and hints that new subgroups/entities in LGESS still remain undiscovered. This article is protected by copyright. All rights reserved.
    Full-text Article · May 2016 · Genes Chromosomes and Cancer
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    Dag Andre Nymoen · Ana Slipicevic · Arild Holth · [...] · Ben Davidson
    [Show abstract] [Hide abstract] ABSTRACT: The objective of this study was to analyze the clinical role of 9 miRNAs (miRs) previously found to be overexpressed in ovarian carcinoma effusions compared to primary ovarian carcinomas. High-grade serous carcinoma effusions (n=148) were analyzed for expression of miR-29a, miR-31, miR-99b, miR-182, miR-210, miR-221, miR-222, miR-224 and miR-342 using quantitative PCR. Expression levels were analyzed for association with clinicopathologic parameters and survival. miR-29a and miR-31 levels were further assessed for association with protein expression of their targets Stathmin and DNA methyltransferase-3A (DNMT3A) by immunohistochemistry and Western blotting, respectively. miRNA levels were unrelated to clinicopathologic parameters. However, higher miR-29a levels were significantly related to longer overall survival in univariate (p=0.007) and Cox multivariate survival analysis (p=0.045). miR-29a levels were inversely related to those of its target DNMT3A (p=0.048), and higher DNMT3A expression was significantly related to poor overall survival in univariate (p=0.03) and Cox multivariate (p=0.016) survival analysis. In contrast, miR-31 levels were directly related to cytoplasmic phospho-Stathmin expression (p=0.029) and unrelated to Stathmin and nuclear phospho-Stathmin, and both Stathmin and phospho-Stathmin expression was unrelated to survival. miR-29a and its target DNMT3A are novel candidate biomarkers of longer and shorter survival, respectively, in metastatic high-grade serous carcinoma.
    Full-text Article · Apr 2016 · Human pathology
  • Ben Davidson · Marna Lill Kjæreng · Mette Førsund · [...] · Vera Maria Abeler
    [Show abstract] [Hide abstract] ABSTRACT: Objectives: To analyze the clinical role of hormone receptors in a large uterine sarcomas series with long-term follow-up. Methods: Protein expression of estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemistry was studied in tissue microarrays from 294 patients diagnosed with uterine sarcoma in Norway from 1970 to 2000 and analyzed for an association with clinicopathologic parameters and outcome. Results: ER and PR were detected in 136 of 291 and 184 of 291 tumors (three noninformative cases each), respectively. Expression was unrelated to histology, patient age, tumor diameter, the degree of atypia, the presence of necrosis or vascular invasion, or mitotic counts. ER and PR expression was unrelated to survival in the analysis of the entire cohort. When survival analysis was confined to stage I leiomyosarcoma (n = 147), higher PR score was significantly related to longer overall survival (OS) (P = .042). Clinicopathologic prognosticators in this group were age (P = .041), tumor diameter (P = .001), and mitotic count (P = .007), with a trend for atypia (P = .087). In Cox multivariate analysis, PR score (P = .019), tumor diameter (P = .013), and mitotic count (P = .002) were independent prognosticators of OS. Conclusions: Hormone receptor expression is not informative of outcome in the analysis of uterine sarcomas of all stages and histologic types. PR expression identifies patients with longer survival in stage I leiomyosarcoma.
    Article · Apr 2016 · American Journal of Clinical Pathology
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    [Show abstract] [Hide abstract] ABSTRACT: Preoperative diagnostics of ovarian neoplasms rely on ultrasound imaging and the serum biomarkers CA125 and HE4. However, these markers may be elevated in non-neoplastic conditions and may fail to identify most non-serous epithelial cancer subtypes. The objective of this study was to identify histotype-specific serum biomarkers for mucinous ovarian cancer. The candidate genes with mucinous histotype specific expression profile were identified from publicly available gene-expression databases and further in silico data mining was performed utilizing the MediSapiens database. Candidate biomarker validation was done using qRT-PCR, western blotting and immunohistochemical staining of tumor tissue microarrays. The expression level of the candidate gene in serum was compared to the serum CA125 and HE4 levels in a patient cohort of prospectively collected advanced ovarian cancer. Database searches identified REG4 as a potential biomarker with specificity for the mucinous ovarian cancer subtype. The specific expression within epithelial ovarian tumors was further confirmed by mRNA analysis. Immunohistochemical staining of ovarian tumor tissue arrays showed distinctive cytoplasmic expression pattern only in mucinous carcinomas and suggested differential expression between benign and malignant mucinous neoplasms. Finally, an ELISA based serum biomarker assay demonstrated increased expression only in patients with mucinous ovarian cancer. This study identifies REG4 as a potential serum biomarker for histotype-specific detection of mucinous ovarian cancer and suggests serum REG4 measurement as a non-invasive diagnostic tool for postoperative follow-up of patients with mucinous ovarian cancer.
    Full-text Article · Mar 2016 · PLoS ONE
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    Dataset: S2 Fig
    [Show abstract] [Hide abstract] ABSTRACT: In Silico analysis of REG4 mRNA expression in the MediSapiens database across healthy human tissue samples (n = 3082). (PDF)
    Full-text Dataset · Mar 2016
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    Dataset: S1 Table
    [Show abstract] [Hide abstract] ABSTRACT: Genes with mucinous specific expression profile in clinical ovarian cancer samples. (XLSX)
    Full-text Dataset · Mar 2016
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    Dataset: S2 Table
    [Show abstract] [Hide abstract] ABSTRACT: Detailed sample description and results of the ELISA assay. (DOCX)
    Full-text Dataset · Mar 2016
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    Dataset: S4 Table
    [Show abstract] [Hide abstract] ABSTRACT: Detailed results of serum ELISA-analysis at multiple time points from one patient. (DOCX)
    Full-text Dataset · Mar 2016
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    Dataset: S3 Table
    [Show abstract] [Hide abstract] ABSTRACT: REG4 cut-off value has been set based on the highest REG4 concentration obtained from healthy male and a larger set of non-mucinous serum controls. (DOCX)
    Full-text Dataset · Mar 2016
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    Dataset: S1 Fig
    [Show abstract] [Hide abstract] ABSTRACT: In Silico analysis of REG4 mRNA expression in the MediSapiens database across malignant human tissue samples (n = 15392). (PDF)
    Full-text Dataset · Mar 2016
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    [Show abstract] [Hide abstract] ABSTRACT: The molecular pathways that contribute to the proliferation and drug response of cancer cells are highly complex and currently insufficiently characterized. We have identified a previously unknown microRNA-based mechanism that provides cancer cells means to stimulate tumorigenesis via increased genomic instability and, at the same time, evade the action of clinically utilized microtubule drugs. We demonstrate miR-493-3p to be a novel negative regulator of mitotic arrest deficient-2 (MAD2), an essential component of the spindle assembly checkpoint that monitors the fidelity of chromosome segregation. The microRNA targets the 3' UTR of Mad2 mRNA thereby preventing translation of the Mad2 protein. In cancer cells, overexpression of miR-493-3p induced a premature mitotic exit that led to increased frequency of aneuploidy and cellular senescence in the progeny cells. Importantly, excess of the miR-493-3p conferred resistance of cancer cells to microtubule drugs. In human neoplasms, miR-493-3p and Mad2 expression alterations correlated with advanced ovarian cancer forms and high miR-493-3p levels were associated with reduced survival of ovarian and breast cancer patients with aggressive tumors, especially in the paclitaxel therapy arm. Our results suggest that intratumoral profiling of miR-493-3p and Mad2 levels can have diagnostic value in predicting the efficacy of taxane chemotherapy.
    Full-text Article · Mar 2016 · Oncotarget
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    Full-text Dataset · Mar 2016
  • [Show abstract] [Hide abstract] ABSTRACT: The objective of this study was to analyze the expression and clinical role of 13 signaling molecules in a large cohort of breast carcinoma patients with long follow-up period. Breast carcinomas (n=410) were analyzed for protein expression of phosphorylated mitogen-activated protein kinases (p-ERK, p-JNK, p-p38) and phosphoinositide 3-kinase (PI3K) signaling pathway proteins (p-AKT, p-mTOR, p-p70S6K), the Bag family proteins BAG-1 and BAG-4/SODD, the anti-apoptotic protein Bcl-2, the inhibitor of apoptosis family member Survivin and the heat shock protein family members HSP27, HSP70 and HSP90. Protein expression was studied for association with clinicopathologic parameters and survival. Significantly higher expression of p-AKT (P<0.001), p-mTOR (P<0.001), p-p70S6K (P<0.001), Bcl-2 (P<0.001), BAG-4/SODD (P<0.001), HSP27 (P<0.001), HSP70 (P=0.012), HSP90 (P<0.001) and Survivin (P=0.004) was found in infiltrating ductal and lobular carcinomas compared to mucinous carcinomas. Bcl-2 expression was significantly higher in grade 1 and 2 compared to grade 3 carcinomas (P<0.001). p-AKT expression was higher in tumors >2 cm (P=0.027), whereas p-mTOR expression was lowest in tumors >5 cm (P=0.019). Higher BAG-4/SODD, HSP70, and HSP90 expression was associated with poor overall survival (P=0.016, P=0.039 and P=0.023, respectively) in univariate analysis, whereas the only independent prognosticator in Cox multivariate survival analysis was tumor diameter (P=0.003). In conclusion, BAG-4/SODD, HSP70, and HSP90 are potential prognostic markers in node-negative breast carcinoma that merit further research.
    Article · Mar 2016 · Human pathology
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    Claire W. Michael · Ben Davidson
    [Show abstract] [Hide abstract] ABSTRACT: Effusions or body cavity fluids are amongst the most commonly submitted samples to the cytology laboratory. Knowledge of proper collection, storage, preservation and processing techniques is essential to ensure proper handling and successful analysis of the sample. This article describes how the effusions should be collected and proper conditions for submission. The different processing techniques to extract the cellular material and prepare slides satisfactory for microscopic evaluation are described such as direct smears, cytospins, liquid based preparations and cell blocks. The article further elaborates on handling the specimens for additional ancillary testing such as immunostaining and molecular tests, including predictive ones, as well as future research approaches.
    Full-text Article · Jan 2016 · Pleura and Peritoneum
  • Article · Jan 2016 · Clinical Cancer Research
  • Yeheli Ravid · Malka Formanski · Yoav Smith · [...] · Ben Davidson
    [Show abstract] [Hide abstract] ABSTRACT: Objective: To compare the microRNA (miRNA) profiles of uterine endometrial stromal sarcoma (ESS) and leiomyosarcoma (LMS), and to compare the miRNA signatures of primary and metastatic uterine LMS. Methods: Eight primary LMS, 9 primary ESS and 8 metastatic LMS were analyzed for miRNA profiles using TaqMan Human miRNA Array Cards. Findings for 20 differentially expressed miRNAs were validated in a series of 44 uterine sarcomas (9 primary uterine ESS, 17 primary uterine LMS, 18 metastatic LMS) using qPCR. Frizzled-6 protein expression was analyzed in 30 LMS (15 primary, 15 metastases). Frizzled-6 was silenced in SK-LMS-1 uterine LMS cells using siRNA and the effect on invasion, wound healing and matrix metalloproteinase (MMP) activity was assessed. Results: Ninety-four miRNAs were significantly differentially expressed in ESS and LMS, of which 76 were overexpressed in ESS and 18 overexpressed in LMS. Forty-nine miRNAs were differentially expressed in primary and metastatic LMS, of which 45 were overexpressed in primary LMS and 4 in metastases. Differential expression was confirmed for 10/20 miRNA analyzed using qPCR. Frizzled-6 silencing in SK-LMS-1 cells significantly inhibited cellular invasion, wound healing and MMP-2 activity. Conclusions: Differential miRNA signatures of ESS and LMS provide novel data regarding transcriptional regulation in these cancers, based on which new potential diagnostic markers, prognostic biomarkers and therapeutic targets may be explored. Differences in miRNA profiles of primary and metastatic LMS may improve our understanding of disease progression in this aggressive malignancy.
    Article · Jan 2016 · Gynecologic Oncology
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    [Show abstract] [Hide abstract] ABSTRACT: We introduce a novel per-gene measure of intra-gene DNA methylation variability (IGV) based on the Illumina Infinium HumanMethylation450 platform, which is prognostic independently of well-known predictors of clinical outcome. Using IGV, we derive a robust gene-panel prognostic signature for ovarian cancer (OC, n = 221), which validates in two independent data sets from Mayo Clinic (n = 198) and TCGA (n = 358), with significance of p = 0.004 in both sets. The OC prognostic signature gene-panel is comprised of four gene groups, which represent distinct biological processes. We show the IGV measurements of these gene groups are most likely a reflection of a mixture of intra-tumour heterogeneity and transcription factor (TF) binding/activity. IGV can be used to predict clinical outcome in patients individually, providing a surrogate read-out of hard-to-measure disease processes.
    Full-text Article · Dec 2015 · PLoS ONE

Publication Stats

8k Citations

Institutions

  • 2010-2013
    • Oslo University Hospital
      • Department of Pathology
      Kristiania (historical), Oslo, Norway
  • 2008-2009
    • Tel Aviv University
      • Department of Pathology
      Tel Aviv, Tel Aviv, Israel
  • 2003
    • Hebrew University of Jerusalem
      • Faculty of Medicine
      Jerusalem, Jerusalem District, Israel
  • 1999
    • University of Oslo
      • Department of Pathology (PAT)
      Norway