Cancers of unknown primary origin (CUP) are characterized by chromosomal instability (CIN) compared to metastasis of know origin

BACKGROUND: Cancers of unknown primary (CUPs) constitute ~5% of all cancers. The tumors have an aggressive biological and clinical behavior. The aim of the present study has been to uncover whether CUPs exhibit distinct molecular features compared to metastases of known origin. METHODS: Employing genome wide transcriptome analysis, Linear Discriminant Analysis (LDA) and Quadratic Discriminant Analysis (QDA), we defined the putative origins of a large series of CUP and how closely related a particular CUP was to corresponding metastases of known origin. LDA predictions were subsequently used to define a universal CUP core set of differentially expressed genes, that by means of gene set enrichment analysis was exploited to depict molecular pathways characterizing CUP. RESULTS: The analyses show that CUPs are distinct from metastases of known origin. CUPs exhibit inconsistent expression of conventional cancer biomarkers and QDA derived outlier scores show that CUPs are more distantly related to their primary tumor class than corresponding metastases of known origin. Gene set enrichment analysis showed that CUPs display increased expression of genes involved in DNA damage repair and mRNA signatures of chromosome instability (CIN), indicating that CUPs are chromosome unstable compared to metastases of known origin. CONCLUSIONS: CIN may account for the uncommon clinical presentation, chemoresistance and poor outcome in patients with CUP and warrant selective diagnostic strategies and treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1128-x) contains supplementary material, which is available to authorized users

Impact of age‐dependent red blood cell parameters on α‐globin gene genotyping in children

Abstract When screening for α‐thalassemia in children, adult cut‐offs for mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) are generally applied to guide genetic evaluation. However, the normal ranges for MCV and MCH are lower in children than in adults, so we hypothesized that using age‐matched cut‐offs could lead to a more rational diagnostic strategy. The aim of this study was to evaluate if age‐matched cut‐offs could be applied advantageously. Data on children referred to a hemoglobin fractionation at the Department of Clinical Biochemistry, Aarhus University Hospital between 2016–2021 were identified in the laboratory information system. α‐globin gene (HBA1/HBA2) genotyping was performed using multiplex gap‐polymerase chain reaction. A total of 387 children were identified. HBA1/HBA2‐genotyping was performed in 207 children (53%), and α‐thalassemia was diagnosed in 47 children (23%) with −α3.7/αα being the predominant genotype (13%). We found that 23 children had MCV and MCH levels in the normal age‐matched range, and two of these children (9%) were α+ thalassemia carriers with three functional α‐globin genes. Using age‐specific cut‐off levels resulted in a reduction of 23 (11%) genotypes performed. In conclusion, applying age‐matched cut‐offs for MCV and MCH when screening children for α‐thalassemia lead to 11% fewer genotypes performed while 9% carriers of α+ thalassemia (of the medically innocuous genotype −α3.7/αα) would have been overlooked

<b>Deceived by Elevated A1C: Cases of Misdiagnosed Diabetes</b>

A1C is an integrated biomarker for diagnosing diabetes and evaluating glycemic control in people with an established diabetes diagnosis. It has been recommended as one of the diagnostic screening criteria for more than a decade, both by the American Diabetes Association (ADA) and the World Health Organization (WHO) (1–3). However, the use of A1C as a diagnostic and monitoring tool is not without pitfalls. Conditions associated with increased or decreased erythrocyte turnover affect the A1C fraction (4), and in such cases, A1C may not reflect true average plasma glucose (5,6). Furthermore, analytical interference with A1C may occur because of genetic hemoglobin variants or metabolic alterations of hemoglobin (e.g., acetylation by acetylsalicylic acid) (7,8).</p

Early Change in FDG-PET Signal and Plasma Cell-Free DNA Level Predicts Erlotinib Response in EGFR Wild-Type NSCLC Patients

INTRODUCTION: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a treatment option in the second- or third-line palliative setting in EGFR wild-type (wt) non–small cell lung cancer (NSCLC) patients. However, response rates are low, and only approximately 25% will achieve disease control. Early prediction of treatment resistance could accelerate discontinuation of ineffective treatment and reduce unnecessary toxicity. In this study, we evaluated early changes on 18F-fluoro-D-glucose (F-18-FDG) positron emission tomography/computed tomography (PET/CT) and in total plasma cell-free DNA (cfDNA) as markers of erlotinib response in EGFR-wt patients. METHODS: F-18-FDG-PET/CT scans and blood samples were obtained prior to erlotinib initiation and were repeated after 1 week (PET/CT) and 1 to 4 weeks (blood sample) of treatment. Level of cfDNA was measured by droplet digital polymerase chain reaction. Percentage change (%∆) in SULpeak and total lesion glycolysis (TLG) on FDG-PET/CT and in plasma cfDNA was correlated to radiological response, progression-free survival (PFS), and overall survival (OS). RESULTS: Fifty patients were prospectively enrolled. A significant correlation was found between CT response and %∆TLG (P = .003). All patients with early metabolic progression showed radiological progression. Increased %∆TLG and %∆cfDNA were significantly correlated with shorter PFS (P = .002 and P = .004, respectively) and OS (P = .009 and P = .009, respectively). Multivariate analysis indicated %∆cfDNA to be the strongest predictor of OS. CONCLUSION: Early increase in TLG on F-18-FDG-PET/CT correlates with radiological progression, and shorter PFS and OS. Early increase in cfDNA predicts shorter PFS and OS. Both assessments are promising tools for early detection of nonresponders and reduced OS in TKI-treated EGFR-wt NSCLC patients