Showing papers by "Frédéric Charlotte published in 2015"

Reproducible and Sustained Efficacy of Targeted Therapy With Vemurafenib in Patients With BRAFV600E-Mutated Erdheim-Chester Disease

Abstract: Purpose Histiocytoses are rare disorders with heterogeneous prognosis. BRAF V600E mutations have been observed in half of patients with Langerhans cell histiocytosis (LCH) and in 50% to 100% of patients with Erdheim-Chester disease (ECD) patients. We recently reported short-term efficacy of a BRAF inhibitor (vemurafenib) in three patients with multisystemic ECD.

Antiviral therapy is associated with a better survival in patients with hepatitis C virus and B‐cell non‐Hodgkin lymphomas, ANRS HC‐13 lympho‐C study

Abstract: Hepatitis C virus (HCV) infection increases the risk of B-cell non-Hodgkin lymphomas (B-NHL). Antiviral treatment (AT) can induce hematological responses in patients with marginal zone lymphomas (MZL). The ANRS HC-13 Lympho-C study aimed at a better understanding of the impact of AT on HCV associated B-NHL. This multicentric study enrolled 116 HCV-positive patients with B-NHL between 2006 and 2012. Cytological and histological samples were collected for centralized review. At lymphoma diagnosis, median age was 61 years and gender ratio M/F was 1. Cytohistological distribution was marginal zone lymphoma (MZL) n = 45 (39%), diffuse large B-cell lymphoma (DLBCL) n = 45 (39%), and other types n = 26 (22%). MZL patients had more frequent detection of rheumatoid factor (68% vs. 35%; P = 0.001) and more frequently mixed cryoglobulinemia (74% vs. 44%; P = 0.021) than patients with DLBCL. Among patients receiving AT, a sustained virologic response was achieved in 23 of 38 (61%) patients with MZL and in 9 of 17 (53%) with DLBCL (P = 0.42). Three-year overall survival (OS) and progression-free survival were 78% 95%CI [63-88] and 64% [48-76], respectively, without difference between cytohistological groups. Outcome analysis showed a favorable association between OS and AT in all patients (P = 0.05) and in the subgroup of MZL patients only (P = 0.04). Our data support that AT improves the outcomes of HCV-associated NHLs. The impact of new AT regimen with protease inhibitor needs to be investigated in this setting. [clinicalTrials.gov Identification number NCT01545544]

Angioimmunoblastic T-cell lymphoma is the most common T-cell lymphoma in two distinct French information data sets.

Abstract: Reliable information regarding the current prevalence of peripheral T-cell lymphoma (PTCL) entities is missing. Herein we report on the frequency of PTCL entities in France between 2010 and 2013. Using Lymphopath , a national lymphoma network established by the French National Cancer Agency, which

The histiocytosis Erdheim–Chester disease is an inflammatory myeloid neoplasm

Abstract: Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis, characterized by the infiltration of tissues by foamy CD68(+)CD1a(-) histiocytes. (99)Technetium bone scintigraphy revealing almost constant tracer uptake by the long bones is highly suggestive of ECD, and a 'hairy kidney' appearance on abdominal computed tomography scan is observed in about half of all ECD cases. CNS involvement is a strong prognostic factor and independent predictor of death. IFN-α seems to be the best initial treatment for ECD. More than half of all ECD patients carry the BRAF(V600E) mutation. More than 30 patients worldwide harboring this mutation and displaying multisystemic, refractory ECD have been treated with vemurafenib, a BRAF inhibitor, which has proven highly beneficial. Other recurrent mutations of the MAPK and PIK3 pathways (NRAS, PIK3CA) have recently been described. These mutations should lead to a new classification of histiocytic disorders such that Langerhans cell histiocytosis and ECD are classified as inflammatory myeloid neoplasms.

IgG4-related Disease Masquerading as Recurrent Scleritis and Chronic Conjunctivitis

Abstract: Purpose: To report atypical ophthalmologic manifestations and complications of IgG4-related disease (IgG4-RD).Methods: Patients with isolated ophthalmologic involvement of IgG4-RD other than lacrimal or orbital infiltration seen between 2009 and 2011 in a single tertiary center were retrospectively reviewed and their clinical and histological features, treatment, and prognosis were studied.Case reports: Two patients (mean age 56.5 years) were included. One patient presented with recurrent anterior and posterior scleritis, and one patient had chronic conjunctival infiltration. Histopathology demonstrated lymphoplasmacytic proliferation with overexpression of IgG4+ plasma cells. Both patients initially responded to a high dose of oral corticosteroids (1 mg/kg/d). However, one patient required the adjunction of methotrexate and one patient developed an intra-epithelial conjunctival carcinoma on the site of the initial lesion.Conclusion: Patients with atypical presentation of IgG4-RD, such as chronic ...

Primary biliary cirrhosis: proposal for a new simple histological scoring system.

Abstract: Background & Aims A simple and reproducible evaluation of non diagnostic histological lesions related to prognosis remains crucial in primary biliary cirrhosis (PBC). Presently there is no satisfactory simple scoring system analysing them reliably. We elaborated a semi-quantitative scoring system that assesses fibrosis, lymphocytic interface hepatitis (LIH) and ductopenia, separately. This study was aimed to evaluate its intra/interobserver reproducibility and its correlation with the main biochemical data. Methods Liver biopsies from 33 consecutive newly diagnosed PBC patients were independently analysed by five liver pathologists. Fibrosis was classified into five stages (portal/periportal fibrosis/few septa/numerous septa/cirrhosis) and LIH into four grades. The bile duct ratio (BDR), i.e. ratio of the number of portal tracts with ducts to total number of portal tracts, Ludwig's and Scheuer's stages were evaluated. Intra and interobserver agreements were assessed. Histological results were correlated to the biochemical data. Results Most patients had an early disease on clinical and biological parameters. The biopsies measured 23 mm on average (range 12 – 40 mm). Intraobserver reproducibility was substantial for fibrosis (κ = 0.68), LIH (κ = 0.69) and BDR (ICC = 0.69). Interobserver agreement for fibrosis was fair with the 5-class system (κ = 0.36), moderate with a 4-class system (κ = 0.56). moderate for LIH (κ = 0.59) and BDR (ICC = 0.50). Ludwig's and Scheuer's staging showed a fair interobserver agreement (κ = 0.32, κ = 0.31 respectively). Our system showed better correlations with biochemistry than Ludwig's and Scheuer's systems did. Conclusions This simple scoring system, assessing fibrosis, LIH and BDR separately, has a substantial intraobserver and a moderate interobserver reproducibility. Its prognostic relevance has to be evaluated.

Validation of AshTest as a Non-Invasive Alternative to Transjugular Liver Biopsy in Patients with Suspected Severe Acute Alcoholic Hepatitis.

Abstract: Background/Aims According to guidelines, the histological diagnosis of severe alcoholic steatohepatitis (ASH) can require liver biopsy if a specific treatment is needed. The blood test AshTest (BioPredictive, Paris, France) has been initially validated for the non-invasive diagnosis of ASH in a large population of heavy drinkers. The aim was to validate the AshTest accuracy in the specific context of use of patients with suspected severe ASH, in order to reduce the need for transjugular biopsy before deciding treatment. Methods The reference was liver biopsy, performed using the transjugular route, classified according to its histological severity as none, minimal, moderate or severe. Biopsies were assessed by the same experienced pathologist, blinded to simultaneous AshTest results. Results A total of 123 patients with severe clinical ASH (recent jaundice and Maddrey function greater or equal to 32) were included, all had cirrhosis and 80% had EASL histological definition of ASH. 95% of patients received prednisolone; and the 2-year mortality was 63%. The high AshTest performance was confirmed both for the binary outcome [AUROC = 0.803 (95%CI 0.684–0.881)] significantly higher than the AST/ALT AUROC [0.603 (0.462–0.714); P<0.001], and for the severity of ASH-score system by the Obuchowski measures for [mean (SE) 0.902 (0.017) vs. AST/ALT 0.833 (0.023); P = 0.01], as well as for the diagnosis and severity of ballooning, PMN and Mallory bodies. According to attributability of discordances, AshTest had a 2–7% risk of 2 grades misclassification. Conclusion These results confirmed the diagnostic performance of AshTest in cirrhotic patients with severe clinical ASH, in the specific context of use of corticosteroid treatment. AshTest is an appropriate non-invasive alternative to transjugular liver biopsy.

La maladie de Rosai-Dorfman-Destombes est une histiocytose inflammatoire polymorphe : étude phénotypique multicentrique de 47 patients

Abstract: Introduction La maladie de Rosai-Dorfman-Destombes est une histiocytose non langerhansienne, inflammatoire, caracterisee dans sa forme classique par une polyadenopathie debutant dans l’enfance ou chez le jeune adulte avec a l’examen histologique une infiltration des sinus ganglionnaires par des histiocytes CD68 positifs, CD1a negatifs, et des images d’emperipolese. Il s’y associe dans 15 % des cas une auto-immunite. La presentation clinique est cependant parfois eloignee de cette description princeps. Nous avons cherche a decrire le spectre clinique des patients ayant un diagnostic de maladie de Rosai-Dorfman-Destombes. Patients et methodes Nous avons revu les dossiers de patients ayant le diagnostic de maladie de Rosai-Dorfman-Destombes et signales au Centre national de reference des histiocytoses. Les patients etaient classes en : – forme typique s’il existait des adenopathies ; – forme atypique isolee s’il n’existait pas d’adenopathies ; – forme atypique mixte ou reactionnelle si l’examen histologique trouvait des signes respectivement d’une autre histiocytose ou d’une pathologie hematologique associee. Resultats Quarante-sept dossiers ont ete analyses, correspondant a 29 hommes pour 18 femmes d’âge moyen au diagnostic 20,3 ans (de 1 a 60 ans). Les organes atteints etaient : ganglions lymphatiques (n = 32, 68 %), os (n = 9, 19 %), peau (n = 7, 15 %), systeme nerveux central (SNC) (n = 7, 15 %), atteinte ORL (n = 5, 11 %). Vingt-six patients (55 %) presentaient une forme typique, 14 une forme atypique isolee (30 %) dont 7 une atteinte isolee du SNC, 4 une atteinte osseuse, 2 une atteinte de la peau, et 1 une atteinte ORL. Enfin, 7 patients (15 %) presentaient une atteinte atypique associee a une autres histiocytose (n = 5) ou une pathologie hematologique (n = 3 dont 2 maladies de Hodgkin), 1 patient ayant a la fois une histiocytose mixte et un syndrome myeloproliferatif. Les patients etaient traites par corticoides (n = 27, 57 %), vinblastine (n = 7, 15 %), azathioprine (n = 6, 13 %), interferon-alpha (n = 6, 13 %), cladribine (n = 5, 11 %), methotrexate (n = 5, 11 %), antiTNF-alpha (n = 2, 4 %), rituximab (n = 2, 4 %), imatinib mesylate (n = 1). Vingt patients (43 %) n’etaient pas traites ou traites uniquement par la chirurgie ou des traitements topiques. Un patient a presente une amylose renale et est decede d’un choc septique. Discussion Cette etude a mis en evidence que si la moitie des patients ont une presentation clinique similaire a la description princeps decrite par Destombes puis Rosai et Dorfman, il existe egalement des atteintes osseuses et du SNC isolees. Evoquer ce diagnostic impose par ailleurs de rechercher une maladie hematologique associee car les stigmates histologiques de maladie de Rosai-Dorfman-Destombes peuvent etre reactionnels. Enfin, si la maladie de Rosai-Dorfman-Destombes a la reputation d’etre benigne, elle necessite dans plus de la moitie des cas un traitement immunomodulateur dont la pierre angulaire repose sur les corticoides, et peut lorsque l’evolution est prolongee, etre responsable d’amylose. Conclusion Cette etude multicentrique met en evidence que la maladie de Rosai-Dorfman-Destombes est une histiocytose polymorphe dont la presentation clinique est parfois eloignee de la description princeps. Il existe en particulier des formes isolees du SNC. Ce diagnostic peut par ailleurs etre associe a une autre histiocytose ou une pathologie hematologique qui guide alors le traitement. Un registre national est en cours de constitution pour decrire de facon plus large le spectre de la maladie de Rosai-Dorfman-Destombes, les anomalies genetiques, immunologiques et moleculaires associees et le pronostic a long terme.

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma with KIR3DL2 and NKp46 expression in a human immunodeficiency virus carrier.

Abstract: Primary cutaneous aggressive epidermotropic T-cell lymphoma (PCAETCL) is a very rare lymphoma characterized by rapidly growing necrotic cutaneous lesions with an epidermotropic CD8+ T-cell neoplastic infiltrate observed histopathologically. It is associated with a very poor outcome, despite aggressive multi-agent chemotherapy. We report a 49-year-old human immunodeficiency virus (HIV)-infected patient who developed PCAETCL with associated marked vascular injury leading to diffuse purpuric and necrotic lesions complicated by recalcitrant hemophagocytic activation syndrome. The lymphoma strongly and diffusely expressed CD158k/KIR3DL2 at the protein and transcript level and NKp46 transcripts, in addition to CD8 and cytotoxic proteins. We observed a diffuse CD158k/KIR3DL2 protein expression in another case of PAETCL, not associated with immunodeficiency, which was used as a positive control. PCAETCL can develop in HIV-infected patients and may present in vasculitis-like fashion. The possible role of immunosuppression and/or HIV in oncogenesis can be postulated, as patients infected with HIV may develop anti-HIV cytotoxic CD8+ lymphoproliferations. The frequency of CD158k/KIR3DL2 and NKp46 expression in PCAECL remains to be studied in a series of cases, and may represent interesting targets for future treatments.

Hepatitis E infection in patients with severe alcoholic hepatitis: is there a place for systematic screening?

Abstract: BACKGROUND One study has suggested that markers of acute hepatitis E virus (HEV) infection are present in 3.6% of patients with severe alcoholic hepatitis (AH). However, validation of these preliminary results is lacking, as well as the impact of HEV infection on the 6-month survival. AIMS The aims of this study were to evaluate the prevalence of HEV infection markers in an external cohort of patients with histologically proven severe AH and to assess the impact of markers of acute HEV infection on the 6-month survival and the need for liver transplantation (LT). PATIENTS AND METHODS Patients admitted for severe AH from January 2008 to June 2014 were analysed. HEV serology (IgM and IgG) was retrospectively performed. RESULTS Ninety-three patients were analysed (male sex 77.4%, age 53±9 years, Maddrey discriminant function 65±32, MELD score 24±6). Six patients (6.5%) had markers of acute HEV infection (IgM+and IgG+), 11 (11.8%) of past HEV infection (IgG+and IgM-) and 76 (81.7%) had a negative serology (IgM- and IgG-). Initial presentation and biological characteristics were not different between IgM+ and IgM- patients, except for the aspartate aminotransferase level (P<0.001). Markers of acute HEV infection had no impact on response to corticosteroids, 1-, 3- or 6-month survival, and the need for LT. Three patients showed symptomatic acute HEV at onset of acute AH: two were treated with ribavirin during the acute phase: one patient died and one patient underwent LT. CONCLUSION Markers of acute HEV infection were present in 6.5% of patients in our cohort of cirrhotics with histologically proven severe AH, without any impact on short-term or long-term outcome. Whether systematic screening of acute HEV infection in this population should be performed remains an unsolved question.

Measurement of Indoleamine 2, 3 Dioxygenase Activity in Colorectal Cancer: A Controlled Group Study

Abstract: Background: Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme that converts tryptophan (Trp) to kynurenine (Kyn), suppresses antitumor immune responses via depletion of Trp and accumulation of Kyn. We hypothesized that, in colorectal cancer (CRC), IDO activity may serve as a biomarker and thus we compared the IDO activity between patients with CRC and those without CRC. We further assessed the effect of surgical treatment of CRC on IDO activity.Methods: Serum concentrations of Trp and Kyn were measured by high performance liquid chromatography in the sera of 68 patients with CRC (CRC group) and 38 without CRC (Control group) prior surgery (D0) and 7 days after surgery (D7). The IDO activity was estimated by the serum Kyn-to-Trp ratio (Kyn/Trp ratio).Results: At Day 0, serum Kyn concentration was higher in the CRC group than in Control group (1.7 [1.4;2.1] μM vs 1.25 [0.9;1.78] μM, respectively; p=0.004) while no difference in serum concentration of Trp was observed between the two groups. Kyn/Trp ratio (IDO activity) was significantly higher in the CRC group than in Control group. At Day 7 serum concentrations of Trp, Kyn and the Kyn/Trp ratio were not statistically different between the two groups.Conclusion: This study indicates that IDO activity is higher in patients with CRC compared with those without CRC. Surgical treatment impacts the IDO activity with a similar Kyn/Trp ratio in both groups. This study is the first step to larger studies to establish the Kyn/Trp ratio as a reliable serum marker of CRC.

ShearWave elastography in lymph nodes

Abstract: Poster: "ECR 2015 / B-0158 / ShearWave elastography in lymph nodes" by: "F. Houari, O. Lucidarme, J. Gabarre, F. Charlotte, C. Pellot-Barakat, M. Lefort, L. Chami; Paris/FR"

Non-langerhans Cell Histiocytosis-Including Erdheim-Chester Disease- and the Lung

Abstract: Erdheim-Chester disease (ECD) is a rare form of non–Langerhans’ cell histiocytosis that may present with pulmonary involvement. The disease was first described as the “lipoid granulomatose” in 1930. Between then and 2013, more than 500 cases have been reported. Diagnosis of ECD is based on the identification in tissue biopsy of histiocytes, which are typically foamy and immunostain for CD68+ CD1a−. Two signs highly suggestive of ECD are 99Technetium bone scintigraphy showing nearly constant tracer uptake by the long bones and a “hairy kidney” appearance on abdominal CT scan (observed in about half such cases). As opposed to central nervous system infiltration, pulmonary involvement does not appear to be a major prognostic factor in ECD. Interferon α (and/or pegylated interferon α) may be the best first-line therapy for prolonged treatment of ECD and significantly improves survival. The BRAF V600E mutation is an activating mutation of the proto-oncogene BRAF, and is found in more than 50 % of ECD cases. Vemurafenib has been used for a small number of patients harbouring this mutation; inhibition of BRAF activation by vemurafenib was highly beneficial in these cases of severe multisystemic and refractory ECD.

L’étude des manifestations hématologiques dans une série de 133 patients avec une maladie d’Erdheim-Chester met en évidence une association aux pathologies myéloïdes chez 9 patients

Abstract: Introduction La maladie d’Erdheim-Chester (MEC) est une histiocytose non langerhansienne caracterisee par une infiltration tissulaire par des histiocytes spumeux CD68+ CD1a−. La mise en evidence d’une mutation somatique BRAF V600E dans ces histiocytes ainsi que l’association frequente de la MEC a une histiocytose langerhansienne (forme mixte) est a l’origine de l’elaboration d’une nouvelle classification des histiocytoses integrant les mutations de la voie des MAP kinases [1] . Il en resulte l’hypothese que la MEC pourrait etre, comme l’histiocytose langerhansienne, une maladie du ou des progeniteurs medullaires. Nous avons cherche a etudier si la MEC s’associait a d’autres maladies hematologiques. Patients et methodes Parmi les 133 patients ayant une MEC et ayant ete vus a au moins une reprise entre 1992 et janvier 2015, la presence d’une pathologie myeloide etait systematiquement recherchee. Le diagnostic de MEC reposait sur des criteres precedemment decrits [2] . Etait consideree comme pathologie myeloide tout syndrome myeloproliferatif ou myelodyplasique repondant aux criteres diagnostiques internationaux [3] . La presence d’une gammapathie monoclonale etait egalement notee, de meme que la presence d’un diagnostic de myelome sur l’etude du myelogramme ou d’une autre pathologie hematologique (LLC, LNH ou maladie de Hodgkin). Les groupes avec et sans pathologie myeloide etaient compares par Fisher exact test et Mann-Whitney test, la survie entre les 2 groupes etait comparee par log-rank test. Resultats Neuf patients (6,7 %) presentaient une pathologie myeloide : myelodysplasie (n = 2), myelofibrose primitive (n = 2), thrombocytemie essentielle (n = 2), leucemie myelomonocytaire chronique (n = 2), polyglobulie de Vaquez (n = 1). Les 9 patients (100 %) etaient de sexe masculin d’âge median au diagnostic de 64 ans. Trois patients (33 %) presentaient une histiocytose mixte. Neuf patients presentaient une infiltration peri-renale (100 %), 6 une infiltration peri-aortique (66 %), 2 une exophtalmie (20 %), 2 une atteinte du systeme nerveux central (20 %) et 1 un xanthelasma peri-orbitaire (11 %). Chez 4 patients (44 %) la mutation JAK2 V617F etait retrouvee, et chez 5 (55 %) la mutation BRAF V600E. Deux patients presentaient les deux mutations associees. Le sexe masculin (100 % vs 72 %, p = 0,11), l’âge au diagnostic (64 vs 57 ans, p = 0,13) et l’association a une forme mixte (33 % vs 10 %, p = 0,06) n’etaient pas significativement differents dans les groupes avec et sans pathologie myeloide. De meme, la survie n’etait pas modifiee par la presence d’une pathologie myeloide (p = 0,71). Par ailleurs, 15 patients parmi les 133 (12 %) presentaient un pic monoclonal au diagnostic, et parmi eux 2 patients (13 %) avaient un syndrome myeloproliferatif. Une patiente presentait un myelome stade 1. Une patiente avait un diagnostic ancien de LNH en remission. Conclusion La MEC est associee a une prevalence elevee de pathologies hematologiques essentiellement myeloides, notamment de syndromes myeloproliferatifs renforcant l’hypothese que la MEC pourrait etre une maladie du ou des progeniteurs medullaires. Des etudes en cours sur les cultures de progeniteurs medullaires tenteront de repondre a ces questions. Les pathologies myeloides doivent etre recherchees lors du diagnostic et du suivi de la MEC et des formes mixtes.