Showing papers by "Frédéric Charlotte published in 2019"
TL;DR: Histiocytoses are rare diseases involving any tissue or organ of adults or children, and with variable clinical presentation and prognosis, and can be classified into five main groups.
Abstract: Histiocytoses are rare diseases involving any tissue or organ of adults or children, and with variable clinical presentation and prognosis.[1][1] They can be classified into five main groups.[2][2] Most histiocytoses in the L group [HL; this group includes Langerhans cell histiocytosis (LCH),
20 citations
Uppsala University1, Central European Institute of Technology2, Ionian University3, Vita-Salute San Raffaele University4, University of Paris5, Royal Bournemouth Hospital6, National and Kapodistrian University of Athens7, Karolinska Institutet8, Radboud University Nijmegen9, Lyon College10, University of Crete11, Athens Regional Medical Center12, Queen's University Belfast13, University of Montpellier14, University of Cambridge15
TL;DR: Different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories, raising the intriguing possibility that common, pathogen‐triggered, immune‐mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments.
Abstract: The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
18 citations
TL;DR: The demonstration that a somatic point mutation tips the balance of genome-binding pattern provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors.
Abstract: The ETS-domain transcription factors divide into subfamilies based on protein similarities, DNA-binding sequences, and interaction with cofactors. They are regulated by extracellular clues and contribute to cellular processes, including proliferation and transformation. ETS genes are targeted through genomic rearrangements in oncogenesis. The PU.1/SPI1 gene is inactivated by point mutations in human myeloid malignancies. We identified a recurrent somatic mutation (Q226E) in PU.1/SPI1 in Waldenstrom macroglobulinemia, a B-cell lymphoproliferative disorder. It affects the DNA-binding affinity of the protein and allows the mutant protein to more frequently bind and activate promoter regions with respect to wild-type protein. Mutant SPI1 binding at promoters activates gene sets typically promoted by other ETS factors, resulting in enhanced proliferation and decreased terminal B-cell differentiation in model cell lines and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration of DNA binding leading to cellular proliferation and differentiation arrest. Significance: The demonstration that a somatic point mutation tips the balance of genome-binding pattern provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors. This article is highlighted in the In This Issue feature, p. 681
16 citations
TL;DR: No blood test has been shown to be effective in the prediction of primary liver cancer in patients without cirrhosis, so a second test is needed to confirm the diagnosis of liver cancer.
Abstract: BACKGROUND No blood test has been shown to be effective in the prediction of primary liver cancer in patients without cirrhosis. AIM To construct and internally validate two sequential tests for early prediction of liver cancer. These tests enable an algorithm which could improve the performance of the standard surveillance protocol recommended (imaging with or without AFP), limited to patients with cirrhosis. METHODS We performed a retrospective analysis in prospectively collected specimens from an ongoing cohort. We designed an early sensitive high-risk test (LCR1) that combined (using Cox model) hepatoprotective proteins (apolipoproteinA1, haptoglobin) with known risk factors (gender, age, gammaglutamyltranspeptidase), and a marker of fibrosis (alpha2-macroglobulin). To increase the specificity, we then combined (LCR2) these components with alpha-fetoprotein. RESULTS A total of 9892 patients, 85.9% without cirrhosis, were followed up for 5.9 years [IQR: 4.3-9.4]. LCR1 and LCR2 time-dependent AUROCs were not different in construction and validation randomised subsets. Among 2027 patients with high-LCR1 then high-LCR2, 167 cancers (113 with cirrhosis, 54 without cirrhosis) were detected, that is 12 patients needed to screen one cancer. The negative predictive value was 99.5% (95% CI 99.0-99.7) in the 2026 not screened patients (11 cancers without cirrhosis) higher than the standard surveillance, which detected 113 cancers in 755 patients screened, that is seven patients needed to screen one cancer, but with a lower negative predictive value 98.0% (97.5-98.5; Z = 4.3; P < 0.001) in 3298 not screened patients (42 cancers without cirrhosis). CONCLUSIONS In patients with chronic liver disease the LCR1 and LCR2 tests identify those with a high risk of liver cancer, including in those without cirrhosis. NCT01927133.
15 citations
TL;DR: The SteatoTest-2 is simpler and noninferior to the first-generation Steato test for the diagnosis of steatosis, without the limitations of BMI and bilirubin.
Abstract: BACKGROUND Serum biomarkers of steatosis such as the SteatoTest are recommended for large-scale screening studies, because imaging is less accessible and more expensive. AIMS The primary aim of this retrospective analysis of prospective studies was to construct a new SteatoTest-2 that was not inferior to the reference first-generation SteatoTest, but that did not include BMI or bilirubin, as these two components can increase test variability because of the assessment of weight and height and in case of Gilbert syndrome or hemolysis, respectively. PATIENTS AND METHODS Five different subsets of 2997 patients with biopsies were evaluated for test construction and validation, and four to assess the prevalence of steatosis in target populations with increasing risks of steatosis. The performance of the SteatoTest-2 was compared with the reference test, using the noninferiority test (0.10 margin) and the Lin concordance coefficient. RESULTS Areas under the receiver operating characteristic curve of the SteatoTest-2 were noninferior to the reference test (P<0.001). Areas under the receiver operating characteristic curve varied in the SteatoTest-2 and the reference test according to subsets and the prevalence of steatosis, with 0.772 [95% confidence interval (CI): 0.713-0.820] versus 0.786 (95% CI: 0.729-0.832) in the 2997 cases with biopsy and 0.822 (95% CI: 0.810-0.834) versus 0.868 (95% CI: 0.858-0.878) in the 5776 cases including healthy individuals without risk factors of steatosis as controls, respectively. The Lin coefficient was highly concordant (P<0.001), from 0.74 (95% CI: 0.74-0.74) in presumed NAFLD to 0.91 (95% CI: 0.89-0.93) in the construction subset. CONCLUSION The SteatoTest-2 is simpler and noninferior to the first-generation SteatoTest for the diagnosis of steatosis, without the limitations of BMI and bilirubin.
13 citations
TL;DR: Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis characterized by the infiltration of various tissues by CD68-positive (+), CD1a-negative (−) spumous histiocytes.
Abstract: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by the infiltration of various tissues by CD68-positive (+), CD1a-negative (−) spumous histiocytes. Since the discovery that the RAS-RAF-MEK-ERK pathway is altered in almost all cases of ECD, it is now
12 citations
TL;DR: A single-center retrospective study among adult patients with Erdheim-Chester disease treated with BRAF and/or MEK inhibitors between 2012 and 2018 found four patients had clinical manifestations of sarcoidosis occurring under targeted therapy.
Abstract: Almost 70% of patients with Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytosis, harbor the somatic V600E mutation of the BRAF gene. BRAF and MEK inhibitors are dramatically efficacious for treating ECD, particularly in cases of life-threatening manifestations [1]. Sarcoidosis-like disorders have been described during treatments with targeted therapies for cancers [2]. We conducted a single-center retrospective study among adult patients with ECD treated with BRAF and/or MEK inhibitors between 2012 and 2018. During the period of the study, 70 out of 220 patients with ECD were treated with BRAF and/or MEK inhibitor. Four patients had clinical manifestations of sarcoidosis occurring under targeted therapy: 3 had skin lesions, and 1 had mediastinal lymphadenopathies. One patient was excluded because granulomas were not documented despite a deep skin biopsy of subcutaneous nodules. This article is protected by copyright. All rights reserved.
7 citations
TL;DR: There is a significant difference between the prevalence of CD30 positive immunostaining (CD30+ ) in advanced systemic mastocytosis (AdvSM) and in indolent systemic mastocytes (ISM), which correlated with elevated serum tryptase levels (> 50 ng/mL).
Abstract: Mastocytosis is a composite group of heterogeneous diseases defined by the accumulation of abnormal mast cells (MCs) in various tissues. Cutaneous and bone marrow tissues are the most frequently infiltrated in adult patients with systemic mastocytosis (SM) (1) The CD30 (KI-1 antigen) receptor, belongings to the tumor necrosis factor receptor family, may have a role in mastocytosis. CD30 expression in MCs cytoplasm was reported in 2011 by Sotlar K et al. (2) in myeloid neoplasms, including SM. They observed a significant difference between the prevalence of CD30 positive immunostaining (CD30+ ) in advanced systemic mastocytosis (AdvSM) (85%) and in indolent systemic mastocytosis (ISM) (27%), which correlated with elevated serum tryptase levels (> 50 ng/mL). However, the relevance of CD30 expression of MCs in the maculopapular cutaneous lesions of SM patients is still unknown. This article is protected by copyright. All rights reserved.
5 citations
01 May 2019
TL;DR: The algorithm FT‐LCR1‐ LCR2 which sequentially combines the FibroTest and two multi‐analyte‐tests and increased the performance of alfa‐foeto‐protein (AFP) alone, was constructed and internally validated in the prospective FibroFrance cohort.
Abstract: The early non‐invasive prediction of hepatocellular carcinoma in patients with chronic liver disease, without or with cirrhosis, is needed. The algorithm FT‐LCR1‐LCR2 which sequentially combines the FibroTest and two multi‐analyte‐tests (LCR1‐LCR2) and increased the performance of alfa‐foeto‐protein (AFP) alone, was constructed and internally validated in the prospective FibroFrance cohort. The first aim was to externally validate the sensitivity and the 5‐year prognostic value of FT‐LCR1‐LCR2.
3 citations
2 citations
TL;DR: Etude retrospective monocentrique non interventionnelle incluant les patients pris en charge entre 1981 et 2018 dans le service de medecine interne 2 de l’hopital de the Pitie-Salpetriere a Paris, le diagnostic etait certain ou probable chez 19 (70,4 %) et 4 (14,8 %) patientes.
Abstract: Introduction Les perturbations du bilan hepatique sont frequentes au cours du lupus systemique. Elles traduisent le plus souvent une atteinte medicamenteuse, virale ou steatosique du foie mais peuvent egalement etre consecutives a une atteinte hepatique immunologique. L’objectif de cette etude etait de decrire les caracteristiques cliniques, biologiques, histologiques, les complications et l’evolution sous traitement des hepatites auto-immunes au cours du lupus systemique. Materiels et methodes Etude retrospective monocentrique non interventionnelle incluant les patients pris en charge entre 1981 et 2018 dans le service de medecine interne 2 de l’hopital de la Pitie-Salpetriere a Paris. Les criteres d’inclusion etaient : – âge > 18 ans ; – diagnostic de lupus systemique selon les criteres ACR ; – diagnostic prouve ou suspecte d’hepatite auto-immune. Les patients ont ete identifies dans la base de donnees des services de medecine interne et d’anatomopathologie a partir d’une recherche par mots cles. Resultats Soixante et onze patientes atteintes de lupus systemique ont eu une biopsie hepatique au cours de leur suivi. Vingt-sept patientes ont ete incluses : 23 avec une suspicion d’hepatite auto-immune a la biopsie et 4 autres pour lesquelles le diagnostic d’hepatite auto-immune a ete retenu par le clinicien sans que le compte rendu de la biopsie ne soit accessible. L’âge moyen au diagnostic du lupus systemique est de 32,3 ± 17,1 ans. Les manifestations cliniques les plus frequentes etaient articulaires (88,8 %) et cutanees (62,9 %) et l’atteinte renale etait presente chez un tiers des patientes (29,6 %). L’elevation des ALAT et ASAT au diagnostic etait respectivement de 5 [3–10,1] et 5,4 [2–14,4] fois la limite superieure de la normale. Les seuls anticorps specifiques des hepatites auto-immunes retrouves etaient les anti-muscles lisses (n = 14, 52 %). La biopsie hepatique etait compatible avec le diagnostic d’hepatite auto-immune chez 10 (43,4 %) et typique chez 13 (56,5 %) malades. Selon le score international des hepatites auto-immunes de 2008, le diagnostic etait certain ou probable chez 19 (70,4 %) et 4 (14,8 %) patientes. Les traitements les plus frequemment prescrits etaient l’hydroxychloroquine (n = 25, 92,6 %), les corticoides (n = 25, 92,6 %) et l’azathioprine (n = 20, 74 %). Trois malades (11,1 %) ont developpe une cirrhose. Aucune patiente n’est decedee de cause hepatique ou n’a necessite de transplantation hepatique au cours du suivi. Discussion Le diagnostic d’hepatite auto-immune au cours d’un lupus systemique reste difficile. En effet, il existe des elements cliniques et biologiques communs aux deux maladies. Il existe donc un risque de « sur-diagnostiquer » une hepatite auto-immune au cours du lupus selon les criteres de l’IAIHG 2008, qui accordent une place importante aux anticorps antinucleaires et a l’elevation des gammaglobulines. La presence d’anticorps anti-tissus specifiques des hepatites auto-immunes et des signes typiques a la biopsie hepatique sont donc d’un apport diagnostique majeur au cours du lupus systemique. Conclusion L’association lupus systemique et hepatite auto-immune existe avec une majorite d’hepatite auto-immune definie comme probable ou certaine selon la classification internationale de 2008. Le traitement associant hydroxychloroquine, corticoides et azathioprine a permis une evolution hepatique favorable chez la majorite des malades.