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Corpechot C.,University Pierre and Marie Curie | Carrat F.,Unite de Sante Publique | Wendum D.,Service dAnatomie et Cytologie Pathologiques | Chazouilleres O.,University Pierre and Marie Curie | Poupon R.,University Pierre and Marie Curie
Hepatology | Year: 2012

The development of liver fibrosis markers in primary biliary cirrhosis (PBC) is needed to facilitate the assessment of its progression and the effectiveness of new therapies. Here, we investigated the potential usefulness of transient elastography (TE) in the noninvasive evaluation of liver fibrosis stage and disease progression in PBC. We performed, first, a prospective performance analysis of TE for the diagnosis of METAVIR fibrosis stages in a diagnostic cohort of 103 patients and, second, a retrospective longitudinal analysis of repeated examinations in a monitoring cohort of 150 patients followed-up for up to 5 years. All patients were treated with ursodeoxycholic acid. Diagnostic thresholds of liver stiffness in discriminating fibrosis stages ≥F1, ≥F2, ≥F3, and =F4 were 7.1, 8.8, 10.7, and 16.9 kPa, respectively. TE showed high performance and was significantly superior to biochemical markers (e.g., aspartate aminotransferase [AST]/platelet ratio, FIB-4, hyaluronic acid, AST/alanine aminotransferase ratio, and Mayo score) in diagnosing significant fibrosis, severe fibrosis, or cirrhosis. Analysis of the monitoring cohort data set using generalized linear models showed the following: (1) an overall progression rate of 0.48 ± 0.21 kPa/year (P = 0.02) and (2) no significant progression in patients with F0-F1, F2, or F3 stages, but a significant increase (4.06 ± 0.72 kPa/year; P < 0.0001) in cirrhotic patients. A cut-off value of 2.1 kPa/year was associated with an 8.4-fold increased risk of liver decompensations, liver transplantations, or deaths (P < 0.0001, Cox regression analysis). Conclusion: TE is one of the best current surrogate markers of liver fibrosis in PBC. Over a 5-year period, on-treatment liver stiffness appears stable in most noncirrhotic PBC patients, whereas it significantly increases in patients with cirrhosis. Progression of liver stiffness in PBC is predictive of poor outcome. © 2012 American Association for the Study of Liver Diseases.


Fanton d'Andon M.,Institute Pasteur Paris | Quellard N.,Service dAnatomie et Cytologie Pathologiques | Fernandez B.,Service dAnatomie et Cytologie Pathologiques | Ratet G.,Institute Pasteur Paris | And 5 more authors.
PLoS neglected tropical diseases | Year: 2014

Leptospira (L.) interrogans are bacteria responsible for a worldwide reemerging zoonosis. Rodents carry L. interrogans asymptomatically in their kidneys and excrete bacteria in the urine, contaminating the environment. Humans get infected through skin contact and develop a mild or severe leptospirosis that may lead to renal failure and fibrosis. L. interrogans provoke an interstitial nephritis, but the induction of fibrosis caused by L. interrogans has not been studied in murine models. Innate immune receptors from the TLR and NLR families have recently been shown to play a role in the development and progression of tissue fibrosis in the lung, liver and kidneys under different pathophysiological situations. We recently showed that TLR2, TLR4, and NLRP3 receptors were crucial in the defense against leptospirosis. Moreover, infection of a human cell line with L. interrogans was shown to induce TLR2-dependent production of fibronectin, a component of the extracellular matrix. Therefore, we thought to assess the presence of renal fibrosis in L. interrogans infected mice and to analyze the contribution of some innate immune pathways in this process. Here, we characterized by immunohistochemical studies and quantitative real-time PCR, a model of Leptospira-infected C57BL/6J mice, with chronic carriage of L. interrogans inducing mild renal fibrosis. Using various strains of transgenic mice, we determined that the renal infiltrates of T cells and, unexpectedly, TLR and NLR receptors, are not required to generate Leptospira-induced renal fibrosis. We also show that the iNOS enzyme, known to play a role in Leptospira-induced interstitial nephritis, also plays a role in the induction of renal fibrosis. To our knowledge, this work provides the first experimental murine model of sustained renal fibrosis induced by a chronic bacterial infection that may be peculiar, since it does not rely on TLR or NLR receptors. This model may prove useful to test future therapeutic strategies to combat Leptospira-induced renal lesions.


Bossard C.,University of Nantes | Dobay M.P.,Swiss Institute of Bioinformatics | Lamant L.,Hopital Purpan | Missiaglia E.,Swiss Institute of Bioinformatics | And 11 more authors.
Blood | Year: 2014

The extended use of brentuximab-vedotin was reported for CD30+ nonanaplastic peripheralT-celllymphomas(PTCLs)with promising efficacy. CD30 status assessmentis thus a critical factor for therapeutic decision, but the reliability of immunohistochemistry (IHC) in evaluating its expression remains to be defined. This prompted us to investigate the correlation between semiquantitative CD30 protein assessment by IHC andmessengerRNA(mRNA) assessment by micro arraysinacohortof376 noncutaneous PTCLs representative of the main entities. By IHC, CD30 expression was heterogeneous across and within entities and significantly associated with large tumor cell size. In additionto100% anaplastic large-cell lymphomas, 57%ofother PTCL entities were CD30-positive at a 5% threshold. CD30 protein expression was highly correlated to mRNA levels. mRNA levels were bimodal, separating high from low CD30-expressing PTCL cases. Weconclude that IHC is a valuable tool in clinical practice to assess CD30 expression in PTCLs. © 2014 by The American Society of Hematology.


Canaud G.,University of Paris Descartes | Bienaime F.,University of Paris Descartes | Tabarin F.,University of Paris Descartes | Bataillon G.,University Pierre and Marie Curie | And 8 more authors.
New England Journal of Medicine | Year: 2014

Background: Although thrombosis is considered the cardinal feature of the antiphospholipid syndrome, chronic vascular lesions are common, particularly in patients with lifethreatening complications. In patients who require transplantation, vascular lesions often recur. The molecular pathways involved in the vasculopathy of the antiphospholipid syndrome are unknown, and adequate therapies are lacking. Methods: We used double immunostaining to evaluate pathway activation in the mammalian target of rapamycin complex (mTORC) and the nature of cell proliferation in the vessels of patients with primary or secondary antiphospholipid syndrome nephropathy. We also evaluated autopsy specimens from persons who had catastrophic antiphospholipid syndrome. The molecular pathways through which antiphospholipid antibodies modulate the mTORC pathway were evaluated in vitro, and potential pharmacologic inhibitors were also tested in vitro. Finally, we studied the effect of sirolimus in kidney-transplant recipients with the antiphospholipid syndrome. Results: The vascular endothelium of proliferating intrarenal vessels from patients with antiphospholipid syndrome nephropathy showed indications of activation of the mTORC pathway. In cultured vascular endothelial cells, IgG antibodies from patients with the antiphospholipid syndrome stimulated mTORC through the phosphatidyl-inositol 3-kinase (PI3K)-AKT pathway. Patients with antiphospholipid syndrome nephropathy who required transplantation and were receiving sirolimus had no recurrence of vascular lesions and had decreased vascular proliferation on biopsy as compared with patients with antiphospholipid antibodies who were not receiving sirolimus. Among 10 patients treated with sirolimus, 7 (70%) had a functioning renal allograft 144 months after transplantation versus 3 of 27 untreated patients (11%). Activation of mTORC was also found in the vessels of autopsy specimens from patients with catastrophic antiphospholipid syndrome. Conclusions: Our results suggest that the mTORC pathway is involved in the vascular lesions associated with the antiphospholipid syndrome. Copyright © 2014 Massachusetts Medical Society. All rights reserved.


Cornelius J.F.,Heinrich Heine University Düsseldorf | Slotty P.J.,Heinrich Heine University Düsseldorf | Steiger H.J.,Heinrich Heine University Düsseldorf | Hanggi D.,Heinrich Heine University Düsseldorf | And 2 more authors.
Acta Neurochirurgica | Year: 2013

Background: About 90 % of meningiomas are benign (WHO grade I), atypical and anaplastic variants exist (WHO grade II/III, 10 %). Tumour grade has important implications for management. Non-invasive diagnosis of tumour grade is still not feasible. The purpose of this survey was to analyse epidemiological risk factors such as sex, age and location for a higher grade (WHO grade II/III) meningioma in a large surgical series. Methods: A retrospective study comprising 1,663 patients operated on for an intracranial meningioma in a single tertiary-care centre. The population was analysed for correlations including WHO grade, histological subtype, tumour localisation, patient age and gender. Additionally correlations between Ki67 index/WHO grade and localisation were analysed. Results: A binary logistic regression analysis revealed non-skull base localisation (OR 1.779 [CI 1.069-2.960, p = 0.0027]) and age ≥65 years (OR 1.549 [CI 1.214-2.624, p = 0.012]) as significant risk factors for a higher WHO grade. Male gender showed a trend for a higher risk in χ2 analysis. An analysis of the Ki67 index revealed an increased index for non-skull base localisation compared with skull base (p < 0.001). Correlation analysis of Ki67 distribution in WHO grade I meningiomas revealed higher Ki67 indices for non skull base localisation (p = 0.0024). Conclusions: Non-skull base localisation and age ≥65 years are independent risk factors for higher grade meningiomas. In other terms, the malignant potential of skull base meningiomas is low. This information is important when advising a patient about individual treatment options (observation, surgery or radio-surgery) and prognosis. © 2013 Springer-Verlag Wien.


Vilasco M.,French Institute of Health and Medical Research | Communal L.,French Institute of Health and Medical Research | Mourra N.,Service dAnatomie et Cytologie Pathologiques | Courtin A.,French Institute of Health and Medical Research | And 3 more authors.
Breast Cancer Research and Treatment | Year: 2011

Stress enhances glucocorticoid (GC) synthesis, which alters inflammation and immune responses, as well as cellular proliferation and apoptosis in a number of tissues. Increasingly, stress has been associated with cancer progression, and in particular in breast cancer. Consequently, an operational glucocorticoid receptor system in breast tissue influences breast cancer development. In this review, we summarize the data on the GC/GR system in normal and tumoral breast tissue. We also review the molecular mechanisms by which GCs control apoptosis and proliferation in breast cancer models and how GCs alter the chemotherapy of breast cancer treatment when used in combination. Finally, we discuss the participation of GR in breast tumorigenesis under hormone replacement therapy. © Springer Science+Business Media, LLC. 2011.


Matsuzaki S.,CHU Clermont Ferrand | Darcha C.,Service dAnatomie et Cytologie Pathologiques | Maleysson E.,CHU Clermont Ferrand | Canis M.,CHU Clermont Ferrand | Mage G.,CHU Clermont Ferrand
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: Only a few, small, human studies on E-cadherin and β-catenin expression in normal cycling human endometrium have been reported. It remains unclear whether expression of these molecules might be altered in the endometrium of infertile patients with endometriosis. Objectives: The aim of the present study was to investigate E-cadherin and β-catenin expression in the endometrium of infertile patients with endometriosis, those with uterine fibromas, and patients with unexplained infertility. Design: Expression levels of E-cadherin and β-catenin mRNA and/or protein in the endometrium of infertile patients with endometriosis (n = 151), those with uterine fibromas (n = 41), patients with unexplained infertility (n = 9), as well as healthy fertile controls (n = 57) were measured. This study utilized laser capture microdissection, real-time RT-PCR, and immunohistochemistry. Results: No significant differences in E-cadherin or β-catenin mRNA expression in microdissected epithelial cells were observed among the different groups throughout the menstrualcycle. However, very low or no protein expression of E-cadherin, total β-catenin, or dephosphorylated β-catenin in luminal and glandular epithelial cells was detected in the mid-secretory endometrium of healthy fertile controls. E-cadherin, total β-catenin, and dephosphorylated β-catenin protein expression in the mid-secretory endometrium of infertile patients with endometriosis or unexplained infertility was significantly higher compared to that of healthy fertile controls in both luminalandglandular epithelial cells. Conclusions: These findings suggest that impaired down-regulation of E-cadherin and β-catenin protein expression, along with Wnt/β-catenin signaling pathway activation during the window of implantation, might be one of the potential molecular mechanisms of infertility in patients with endometriosis. Copyright © 2010 by The Endocrine Society.


Flejou J.-F.,Service dAnatomie et Cytologie Pathologiques
Histopathology | Year: 2015

Although anal cancer remains a relatively uncommon tumour its frequency is rising, especially in high-risk groups. It is now well recognized that anal squamous cell carcinoma, the largely predominant tumour type, shares many similarities with cancer of the uterine cervix, with a major role for oncogenic human papilloma viruses in both tumours. Anal squamous precancerous lesions have now to be classified with the same criteria and terminology as their cervical counterparts, by using the Lower Anogenital Squamous Terminology (LAST) proposal. Only p16 protein is a useful marker in this setting at the present time. As most cases of anal cancer are treated by non-surgical procedures, pathology has a limited role in the staging of the disease, except for early lesions treated by local excision, and when the sentinel lymph node procedure is undertaken that is still under evaluation. A variety of other tumour types can occur more rarely, with difficult diagnostic issues, solved in most cases by immunohistochemistry. © 2015 John Wiley & Sons Ltd.


Sevestre H.,Service dAnatomie et Cytologie Pathologiques | Ikoli J.-F.,Service dAnatomie et Cytologie Pathologiques | Al Thakfi W.,Service dAnatomie et Cytologie Pathologiques
Journal de Gynecologie Obstetrique et Biologie de la Reproduction | Year: 2013

Most tumors of the ovary presumed benign according to clinical, biological and imaging data are cysts. A cyst is a newly formed cavity lined by epithelium. It tends to enlarge, and can undergo torsion, rupture and haemorrhage. Most prevalent cystic lesions, i.e. inclusion cysts, serous or mucinous cystadenomas, endometriotic cysts, mature teratoma and other cysts are described. Diagnostic methods of cytology and pathology are described and evaluated: intraoperative examination of cystic and peritoneal fluids are not recommended; intraoperative consultation can be performed on solid parts or implants, if the pathologist is familiar with these lesions, or if primary carcinoma is known. The value of intraoperative examination is good in benign and cancer cases, but unsatisfactory in borderline lesions, especially of mucinous type. Cryopreservation of ovarian tissue can be performed to preserve tumoral and normal tissue in Biobank for research protocol, or to maintain fertility through follicle preservation, in aseptic conditions. Transfer of samples towards the pathology laboratory can be performed either and preferably in fresh state, or in vacuum sealed bags at +4 C allowing a 2-day delay, or after immersion in a 15 × volume of 4% formalin. Cytological samples must be collected on citrate and sent immediately to the pathology laboratory, or fixed volume/volume in of absolute alcohol. The pathologist and the surgeon must collaborate to obtain good practice: intact labelled sample, accompanied by clinical information, transfer according to best local conditions, judicious use of intraoperative examination, knowing its possibilities and limitations, no excess delay of pathology report, even in difficult cases requiring expert opinion. © 2013 Elsevier Masson SAS. All rights reserved.


The evaluation of prognosis is essential for the management of a patient with a neuroendocrine tumor, especially digestive, in which the risk of malignancy is significant. Three validated histoprognostic factors are available from the pathological examination: morphological differentiation status, histological grade, and pTNM stage. Numerous prognostic biomarkers have been proposed in the literature but none has been transposed to clinical practice. In the sameway, among the candidate predictive biomarkers, only MGMT is an emerging biomarker, which may be useful for the prediction of the response to temozolomide. © 2013 Springer-Verlag France.

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