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      Circulating cell-free BRAF V600E as a biomarker in children with Langerhans cell histiocytosis

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          Abstract

          The BRAFV600E mutation is reported in half of patients with Langerhans cell histiocytosis (LCH). This study investigated the detection of the BRAFV600E allele in circulating cell-free (ccf) DNA in a paediatric LCH cohort. Children with BRAFV600E -mutated LCH were investigated to detect ccf BRAFV600E at diagnosis (n = 48) and during follow-up (n = 17) using a picolitre-droplet digital PCR assay. At diagnosis, ccf BRAFV600E was positive in 15/15 (100%) patients with risk-organ positive multisystem (RO+ MS) LCH, 5/12 (42%) of patients with RO- MS LCH and 3/21 (14%) patients with single-system (SS) LCH (P < 0·001, Fisher's exact test). The positive BRAFV600E load was higher for RO+ patients (mean, 2·90%; range, 0·04-11·4%) than for RO- patients (mean, 0·16%; range, 0·01-0·39) (P = 0·003, Mann-Whitney U test). After first-line vinblastine-steroid induction therapy, 7/7 (100%) of the non-responders remained positive for ccf BRAFV600E compared to 2/4 (50%) of the partial-responders and 0/4 of the complete responders (P = 0·002, Fisher's exact test). Six children treated with vemurafenib showed a clinical response that was associated with a decrease in the ccf BRAFV600E load at day 15. Thus, ccf BRAFV600E is a promising biomarker for monitoring the response to therapy for children with RO+ MS LCH or RO- LCH resistant to first-line chemotherapy.

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          Multiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients.

          Multiplex digital PCR (dPCR) enables noninvasive and sensitive detection of circulating tumor DNA with performance unachievable by current molecular-detection approaches. Furthermore, picodroplet dPCR facilitates simultaneous screening for multiple mutations from the same sample. We investigated the utility of multiplex dPCR to screen for the 7 most common mutations in codons 12 and 13 of the KRAS (Kirsten rat sarcoma viral oncogene homolog) oncogene from plasma samples of patients with metastatic colorectal cancer. Fifty plasma samples were tested from patients for whom the primary tumor biopsy tissue DNA had been characterized by quantitative PCR. Tumor characterization revealed that 19 patient tumors had KRAS mutations. Multiplex dPCR analysis of the plasma DNA prepared from these samples identified 14 samples that matched the mutation identified in the tumor, 1 sample contained a different KRAS mutation, and 4 samples had no detectable mutation. Among the tumor samples that were wild type for KRAS, 2 KRAS mutations were identified in the corresponding plasma samples. Duplex dPCR (i.e., wild-type and single-mutation assay) was also used to analyze plasma samples from patients with KRAS-mutated tumors and 5 samples expected to contain the BRAF (v-raf murine sarcoma viral oncogene homolog B) V600E mutation. The results for the duplex analysis matched those for the multiplex analysis for KRAS-mutated samples and, owing to its higher sensitivity, enabled detection of 2 additional samples with low levels of KRAS-mutated DNA. All 5 samples with BRAF mutations were detected. This work demonstrates the clinical utility of multiplex dPCR to screen for multiple mutations simultaneously with a sensitivity sufficient to detect mutations in circulating DNA obtained by noninvasive blood collection.
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            Cell-free DNA in the blood as a solid tumor biomarker--a critical appraisal of the literature.

            Circulating cell-free DNA (cfDNA) has been suggested as a cancer biomarker. Several studies assessed the usefulness of quantitative and qualitative tumor-specific alterations of cfDNA, such as DNA strand integrity, frequency of mutations, abnormalities of microsatellites, and methylation of genes, as diagnostic, prognostic, and monitoring markers in cancer patients. Most of the papers that could be evaluated in this review resulted in a positive conclusion. However, methodical diversity without the traceability of data and differently designed and often underpowered studies resulted in divergent results between studies. In addition, the limited diagnostic sensitivity and specificity of cfDNA alterations temper the effusive hope of novel tumor markers, raising similar issues as those for other tumor markers. To validate the actual clinical validity of various cfDNA alterations as potential cancer biomarkers in practice for individual tumor types, the main problems of the observed uncertainties must be considered in future studies. These include methodical harmonization concerning sample collection, processing, and analysis with the traceability of measurement results as well as the realization of well-designed prospective studies based on power analysis and sample size calculations. 2010 Elsevier B.V. All rights reserved.
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              Is Open Access

              Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net

              Langerhans Cell Histiocytosis (LCH) is an orphan disease of clonal dendritic cells which may affect any organ of the body. Most of the knowledge about the diagnosis and therapy is based on pedriatic studies. Adult LCH patients are often evaluated by physicians who focus on only the most obviously affected organ without sufficient evaluation of other systems, resulting in patients being underdiagnosed and/or incompletely staged. Furthermore they may be treated with pediatric-based therapies which are less effective and sometimes more toxic for adults. The published literature on adult LCH cases lacks a comprehensive discussion on the differences between pediatric and adult patients and there are no recommendations for evaluation and comparative therapies. In order to fill this void, a number of experts in this field cooperated to develop the first recommendations for management of adult patients with LCH. Key questions were selected according to the clinical relevance focusing on diagnostic work up, therapy, and follow up. Based on the available literature up to December 2012, recommendations were established, drafts were commented by the entire group, and redrafted by the executive editor. The quality of evidence of the recommendations is predominantly attributed to the level of expert opinion. Final agreement was by consensus.
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                Author and article information

                Journal
                British Journal of Haematology
                Br J Haematol
                Wiley
                00071048
                August 2017
                August 2017
                April 25 2017
                : 178
                : 3
                : 457-467
                Affiliations
                [1 ]French Reference Centre for Langerhans Cell Histiocytosis; Trousseau Hospital; Paris France
                [2 ]EA4340; UVSQ, Université Paris-Saclay; Boulogne-Billancourt France
                [3 ]Department of Paediatric Haematology and Oncology; Trousseau Hospital; Assistance Publique-Hôpitaux de Paris; Paris France
                [4 ]Pathology Department; Ambroise Paré Hospital; Assistance Publique-Hôpitaux de Paris; Boulogne-Billancourt France
                [5 ]Laboratory of Haematology; Trousseau Hospital; Assistance Publique-Hôpitaux de Paris; Paris France
                [6 ]INSERM UMR-S1147; CNRS SNC 5014; Université Paris Sorbonne Cité; Paris France
                [7 ]Department of Paediatric Haematology and Oncology; Centre Hospitalo-Universitaire de Toulouse; Toulouse France
                [8 ]Department of Paediatric Haematology and Oncology; Centre Hospitalo-Universitaire de Bordeaux; Bordeaux France
                [9 ]Department of Paediatric Haematology and Oncology; Centre Hospitalo-Universitaire de Grenoble; Grenoble France
                [10 ]Department of Paediatric Haematology and Oncology; Centre Hospitalo-Universitaire de Nice; Nice France
                [11 ]Department of Paediatric Haematology and Oncology; Centre Hospitalo-Universitaire de Tours; Tours France
                [12 ]Department of Paediatric Immunology; Haematology and Rheumatology; Necker Hospital, Assistance Publique-Hôpitaux de Paris; Paris France
                [13 ]Department of Paediatric Haematology and Oncology; Centre Hospitalo-Universitaire d'Amiens; Amiens France
                [14 ]Department of Paediatric Haematology and Oncology; Centre Hospitalo-Universitaire de Strasbourg; Strasbourg France
                [15 ]Department of Paediatric Haematology and Oncology; Centre Hospitalo-Universitaire de Nantes; Nantes France
                [16 ]Department of Paediatric; Hôpital Arnaud de Villeneuve; Montpellier France
                Article
                10.1111/bjh.14695
                28444728
                b6afb40c-7d9f-493e-a382-8ef35c1a4523
                © 2017

                http://doi.wiley.com/10.1002/tdm_license_1.1

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