Integrative molecular and functional profiling of ERBB2-amplified breast cancers identifies new genetic dependencies.

Overexpression of the receptor tyrosine kinase ERBB2 (also known as HER2) occurs in around 15% of breast cancers and is driven by amplification of the ERBB2 gene. ERBB2 amplification is a marker of poor prognosis, and although anti-ERBB2-targeted therapies have shown significant clinical benefit, de novo and acquired resistance remains an important problem. Genomic profiling has demonstrated that ERBB2+ve breast cancers are distinguished from ER+ve and 'triple-negative' breast cancers by harbouring not only the ERBB2 amplification on 17q12, but also a number of co-amplified genes on 17q12 and amplification events on other chromosomes.

A review of the ecological effects of radiofrequency electromagnetic fields (RF-EMF).

Objective: This article presents a systematic review of published scientific studies on the potential ecological effects of radiofrequency electromagnetic fields (RF-EMF) in the range of 10 MHz to 3.6 GHz (from amplitude modulation, AM, to lower band microwave, MW, EMF).

Methods: Publications in English were searched in ISI Web of Knowledge and Scholar Google with no restriction on publication date.

Reliability of core needle biopsy for determining ER and HER2 status in breast cancer.

Background: Several studies have assessed the concordance of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status between core needle biopsy (CNB) and resection specimens, usually in small patient series and with discordant results.

Patients And Methods: ER and HER2 status determined on CNB and tissue micro-arrays of resected tumors were compared for patients treated at the Leiden University Medical Center (LUMC). When results were discordant, whole-sized slides were analyzed.

Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 Working Group Statement.

The 2012 IMPAKT task force investigated the medical usefulness of current methods for the classification of breast cancer into the 'intrinsic' molecular subtypes (luminal A, luminal B, basal-like and HER2). A panel of breast cancer and/or gene expression profiling experts evaluated the analytical validity, clinical validity and clinical utility of two approaches for molecular subtyping of breast cancer: the prediction analysis of microarray (PAM)50 assay and an immuno-histochemical (IHC) surrogate panel including oestrogen receptor (ER), HER2 and Ki67. The panel found the currently available evidence on the analytical validity and clinical utility of Ki67 based on a 14% cut-off and PAM50 to be inadequate.

Modeling toxicity of binary metal mixtures (Cu(2+) -Ag(+) , Cu(2+) -Zn(2+) ) to lettuce, Lactuca sativa, with the biotic ligand model.

The biotic ligand model (BLM) was applied to predict metal toxicity to lettuce, Lactuca sativa. Cu(2+) had the lowest median effective activity (EA50(M) ), compared with Ag(+) and Zn(2+) (EA50(Cu)  = 2.60 × 10(-8) M, EA50(Ag) = 1.

Integration of clinical and gene expression data has a synergetic effect on predicting breast cancer outcome.

Breast cancer outcome can be predicted using models derived from gene expression data or clinical data. Only a few studies have created a single prediction model using both gene expression and clinical data. These studies often remain inconclusive regarding an obtained improvement in prediction performance.

Multimetal accumulation in crustaceans in surface water related to body size and water chemistry.

Many relationships of bioaccumulation of metals have been derived in the past, but verification in the field is often lacking. In the present study, the authors collected field data on bioaccumulation in caged Daphnia magna and Gammarus roeseli in 12 different contaminated brooks. Besides generating a comprehensive data set on bioaccumulation for these species, the authors also checked whether the bioavailability at the biotic ligand is useful to explain differences in observed bioaccumulation.

The landscape of cancer genes and mutational processes in breast cancer.

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored.

Determining sensitivity and specificity of HER2 testing in breast cancer using a tissue micro-array approach.

Introduction: Overexpression of the human epidermal growth factor receptor 2 (HER2) as a result of HER2 gene amplification is associated with a relatively poor prognosis in breast cancer and is predictive of HER2-targeting therapy response. False-positive rates of up to 20% for HER2 testing have been described. HER2-testing laboratories are therefore encouraged to participate in external quality control schemes in order to improve HER2-testing standardization.

Prognosis and prognostic factors of patients with mesothelioma: a population-based study.

Background: It is important to regularly update survival estimates of patients with malignant mesothelioma as prognosis may vary according to epidemiologic factors and diagnostic and therapeutic management.

Methods: We assessed overall (baseline) survival as well as related prognostic variables in a large cohort of 1353 patients with a confirmed diagnosis of malignant mesothelioma between 2005 and 2008.

Results: About 50% of the patients were 70 years or older at diagnosis and the median latency time since start of asbestos exposure was 49 years.

Simplification of biotic ligand models of Cu, Ni, and Zn by 1-, 2-, and 3-parameter transfer functions.

Biotic ligand models for calculation of watertype-specific no effect concentrations are recognized as a major improvement in risk assessment of metals in surface waters. Model complexity and data requirement, however, hamper the regulatory implementation. To facilitate regulatory use, biotic ligand models (BLM) for the calculation of Ni, Cu, and Zn HC5 values were simplified to linear equations with an acceptable level of accuracy, requiring a maximum of 3 measured water chemistry parameters.

Locoregional recurrence after breast-conserving therapy remains an independent prognostic factor even after an event free interval of 10 years in early stage breast cancer.

Introduction: Locoregional recurrence (LRR) after breast-conserving therapy is a well-known independent risk factor associated with unfavourable long-term outcome. Controversy exists concerning the prognostic impact of a LRR after a very long event-free interval.

Method: Patients who underwent breast-conserving therapy for early stage breast cancer were pooled from four European Organisation for Research and Treatment of Cancer (EORTC) Breast Group trials.

Functional characterization of the 19q12 amplicon in grade III breast cancers.

Introduction: The 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. This amplicon comprises nine genes, including cyclin E1 (CCNE1), which has been proposed as its 'driver'. The aim of this study was to identify the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harbouring their amplification.

Predictive factors for local recurrence in breast cancer.

Risk factors for local recurrence in breast cancer after breast conserving therapy (BCT) differ from those for local recurrence after mastectomy. To better guide optimal treatment of individual patients, it is desirable to identify patients at high risk for local recurrence. Several clinical and histopathologic factors, such as young age and presence of ductal carcinoma in situ, are known to be predictors for local recurrence after BCT.

Search for a gene expression signature of breast cancer local recurrence in young women.

Purpose: A gene expression signature, predictive for local recurrence after breast-conserving treatment, has previously been identified from a series of 165 young patients with breast cancer. We evaluated this signature on both another platform and an independent series, compared its performance with other published gene-sets, and investigated the gene expression profile of a larger data set.

Experimental Design: Gene expression tumor profiles were obtained on 148 of the initial 165 Dutch patients and on an independent validation series of 195 French patients.

HER2 testing in gastric cancer: a practical approach.

Trastuzumab in combination with capecitabine or 5-fluorouracil and cisplatin is approved by the European Medicines Agency for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry 3+ or immunohistochemistry 2+/fluorescence in situ hybridization-positive or immunohistochemistry 2+/silver in situ hybridization-positive) metastatic adenocarcinoma of the stomach or gastro-esophageal junction. Approvals are underway in other countries, with recent approvals granted in the United States and Japan. Experience and data from trastuzumab use in breast cancer have highlighted the importance of quality HER2 testing and scoring to ensure accurate identification of patients eligible for treatment.

Linking land use with pesticides in Dutch surface waters.

Compared with other European countries The Netherlands has a relatively high level of pesticide consumption, particularly in agriculture. Many of the compounds concerned end up in surface waters. Surface water quality is routinely monitored and numerous pesticides are found to be present in high concentrations, with various standards being regularly exceeded.

Predicting effects of cations on copper toxicity to lettuce (Lactuca sativa) by the biotic ligand model.

A biotic ligand model (BLM) was developed to estimate Cu toxicity to lettuce (Lactuca sativa) in terms of root elongation after 4 d of exposure. Effects of Na(+), K(+), Ca(2+), and Mg(2+) on Cu toxicity were examined. The addition of these cations resulted in a 50-fold difference in the copper median effective activity (EC50 cu2+).

Participation and yield of colonoscopy versus non-cathartic CT colonography in population-based screening for colorectal cancer: a randomised controlled trial.

Background: Screening for colorectal cancer is widely recommended, but the preferred strategy remains unidentified. We aimed to compare participation and diagnostic yield between screening with colonoscopy and with non-cathartic CT colonography.

Methods: Members of the general population, aged 50-75 years, and living in the regions of Amsterdam or Rotterdam, identified via the registries of the regional municipal administration, were randomly allocated (2:1) to be invited for primary screening for colorectal cancer by colonoscopy or by CT colonography.

External validation of Adjuvant! Online breast cancer prognosis tool. Prioritising recommendations for improvement.

Background: Adjuvant! Online is a web-based application designed to provide 10 years survival probability of patients with breast cancer. Several predictors have not been assessed in the original Adjuvant! Online study. We provide the validation of Adjuvant! Online algorithm on two breast cancer datasets, and we determined whether the accuracy of Adjuvant! Online is improved with other well-known prognostic factors.

Systematic analysis of breast cancer morphology uncovers stromal features associated with survival.

The morphological interpretation of histologic sections forms the basis of diagnosis and prognostication for cancer. In the diagnosis of carcinomas, pathologists perform a semiquantitative analysis of a small set of morphological features to determine the cancer's histologic grade. Physicians use histologic grade to inform their assessment of a carcinoma's aggressiveness and a patient's prognosis.

Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients.

Gene signatures derived from cancer stem cells (CSCs) predict tumor recurrence for many forms of cancer. Here, we derived a gene signature for colorectal CSCs defined by high Wnt signaling activity, which in agreement with previous observations predicts poor prognosis. Surprisingly, however, we found that elevated expression of Wnt targets was actually associated with good prognosis, while patient tumors with low expression of Wnt target genes segregated with immature stem cell signatures.

HER2 gene amplification in patients with breast cancer with equivocal IHC results.

Aims: Equivocal human epidermal growth factor receptor 2 protein (HER2) (2+) immunohistochemistry (IHC) is subject to significant interobserver variation and poses a challenge in obtaining a definitive positive or negative test result. This equivocal test result group accounts for approximately 15% of all tumours, and for optimal guidance of HER2 targeted therapy, a further analysis of quantification of gene copy number and amplification status is needed for patients with early or metastatic breast cancer.

Methods: 553 breast-cancer specimens with equivocal HER2 IHC(2+) test results were collected and subsequently centrally retested by chromogenic in situ hybridisation (CISH), and HER2 gene copy numbers per tumour cell nucleus were determined.

Spatial and temporal variation of watertype-specific no-effect concentrations and risks of Cu, Ni, and Zn.

Geographical and temporal variations in metal speciation were calculated and water-type specific sensitivities were derived for a range of aquatic species, using surveillance water chemistry data that cover almost all surface water types in The Netherlands. Biotic ligand models for Cu, Zn, and Ni were used to normalize chronic no-effect concentrations (NOEC) determined in test media toward site-specific NOEC for 372 sites sampled repeatedly over 2007-2010. Site-specific species sensitivity distributions were constructed accounting for chemical speciation.