Nathalie Sturm

University Joseph Fourier - Grenoble 1, Grenoble, Rhône-Alpes, France

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Publications (102)500.7 Total impact

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    ABSTRACT: Background & aims Fibrosis blood tests have been validated in chronic hepatitis C. Their diagnostic accuracy is less documented in hepatitis B. The aim of this study was to describe the diagnostic performance of Fibrotest®, Fibrometer® and Hepascore® for liver fibrosis in hepatitis B compared to hepatitis C. Methods 510 patients mono-infected with hepatitis B or C and matched on fibrosis stage were included. Blood tests were performed the day of the liver biopsy. Histological lesions were staged according to METAVIR. Results Fibrosis stages were distributed as followed: F0 n=76, F1 n=192, F2 n=132, F3 n=54, F4 n=56. Overall diagnostic performance of blood tests were similar between hepatitis B and C with AUROC ranging from 0.75 to 0.84 for significant fibrosis, 0.82 to 0.85 for extensive fibrosis and 0.84 to 0.87 for cirrhosis. Optimal cut-offs were consistently lower in hepatitis B compared to hepatitis C, especially for the diagnosis of extensive fibrosis and cirrhosis, with decreased sensitivity and negative predictive values. More hepatitis B than C patients with F ⩾3 were underestimated: Fibrotest®: 47% versus 26%, Fibrometer®: 24% versus 6%, Hepascore®: 41% versus 24%, p<0.01. Multivariate analysis showed that hepatitis B (0R 3.4, CI95% 1.2-19.2, p<0.02) and low γGT (OR 7.3, CI95% 2.0-27.0, p<0.003) were associated with fibrosis underestimation. Conclusion Overall the diagnostic performance of blood tests is similar in hepatitis B and C. The risk of underestimating significant fibrosis and cirrhosis is however greater in hepatitis B and cannot be entirely corrected by the use of more stringent cut-offs.
    Journal of Hepatology 07/2014; DOI:10.1016/j.jhep.2014.02.029 · 9.86 Impact Factor
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    ABSTRACT: During chronic hepatitis C virus (HCV) infection, the role of intra-hepatic (IH) natural killer (NK) cells is still controversial. To clarify their functions, we investigated anti-viral and cytotoxic activity of NK cells in human fresh liver biopsies. We compared the functions of IH-NK cells in HCV-infected and NASH patients in physiological conditions as well as after stimulation using flow cytometric and immunohistochemical analyses. Interestingly, few IH-NK cells produced anti-viral cytokine IFN-γ in HCV-infected patients similarly as in non-infected individuals. Spontaneous degranulation activity was extremely low in peripheral NK cells compared to IH-NK cells, and was significantly higher in IH-NK cells from HCV-infected patients compared to non-infected individuals. Immunohistochemical analysis revealed that perforin granules were polarized at the apical pole of IH-NK cells. The presence of CD107a and perforin in IH-NK cells demonstrated that NK cells exerted a cytolytic activity at the site of infection. Importantly, IH-NK cell functions from HCV-infected patients were inducible by specific exogenous stimulations. Upon ex vivo K562 target cell stimulations, the number of degranulating NK cells was significantly increased in the pool of IH-NK cells compared to circulating NK cells. Interestingly, after stimulation, the frequency of IFN-γ-producing IH-NK cells in HCV-infected patients was significantly higher at early stage of inflammation whereas the spontaneous IH-NK cell degranulation activity was significantly impaired in patients with highest inflammation and fibrosis Metavir scores. Our study highlights that some IH-NK cells in HCV-infected patients are able to produce INF-γ and degranulate and that those two activities depend on liver environment including the severity of liver injury. Thus, we conclude that critical roles of IH-NK cells have to be taken into account in the course of the liver pathogenesis associated to chronic HCV infection.
    PLoS ONE 04/2014; 9(4):e95614. DOI:10.1371/journal.pone.0095614 · 3.53 Impact Factor
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    ABSTRACT: Background. The polymorphisms of IFNL4 are strongly associated with both spontaneous hepatitis C virus clearance and response to peg-IFN-α/ribavirin treatment. To further establish the biological effects of the IFNL4 and rs1297860 variations, we studied the activity of liver immune cells.Methods. Fresh liver samples were collected from HCV-infected patients before any treatment and from NASH patients as controls. Degranulation activity of each lymphocyte type was assessed by the surface expression of CD107a. IFNL4 polymorphisms and HCV genotypes were determined.Results. In liver, frequency of CD107a(+) immune cells was significantly higher in HCV- patients compared to NASH patients. Higher degranulation activity was observed in lymphocytes of HCV patients with favorable IFNL4 genotypes compared to patients with unfavorable genotypes. Multivariate regression analyses indicated that serum ALT levels were dependent on both Metavir Activity score and frequency of CD107a positive NKT cells. The high level of degranulation activity observed before treatment was associated with a high HCV RNA decline at the early stage of peg-IFN-α/ribavirin treatment in patients with favorable genotypes.Conclusions. These data underline that intra-hepatic lymphocyte degranulation activity in HCV-infected patients is associated with IFNL4 polymorphisms and contributes to the clearance of HCV in patients with favorable genotypes under antiviral therapy.
    The Journal of Infectious Diseases 01/2014; 209(12). DOI:10.1093/infdis/jiu016 · 5.85 Impact Factor
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    ABSTRACT: Morphometry provides an objective evaluation of fibrosis in liver diseases. We developed an image analysis algorithm using automated thresholding and segmentation to separately quantify the areas and the fractal dimensions of portal-bridging fibrosis and perisinusoidal fibrosis in chronic hepatitis C liver biopsies. We studied 427 digitized liver biopsies and compared the automated measures of the different fibrosis compartments with (1) the Metavir F (fibrosis) and A (activity) histological scores, (2) the digitally assessed area of steatosis, and (3) the liver stiffness measured by elastography (Fibroscan). The perisinusoidal fibrosis area was higher than that of portal fibrosis in stages ≤F2; it reached its highest value in F2 stage and stabilized thereafter. The F3 stage was characterized by equal proportions of portal-bridging and perisinusoidal fibrosis, whereas portal-bridging area was predominant in cirrhosis. Measurement of portal-bridging fibrosis showed highly significantly different values between contiguous F stages; the ratio of portal-bridging fibrosis/perisinusoidal fibrosis displayed less overlap between Metavir stages than did the whole fibrosis area values. Fractal dimension showed that portal-bridging fibrosis tended to display a homogeneous surface-like spatial organization, whereas perisinusoidal fibrosis appeared more heterogeneous according to stage and curvilinear. The portal-bridging fibrosis area was low in cases with low Metavir activity and little steatosis, and became predominant with increasing activity and steatosis. Using stepwise multiple linear regression analysis, the liver stiffness was independently correlated to the portal-bridging fibrosis area (first step, P<0.001), the steatosis area (second step, P<0.001), and the Metavir A grade (third step, P=0.001), but not to the perisinusoidal fibrosis area. Automated quantification in a large cohort of chronic hepatitis C showed that perisinusoidal fibrosis progressively grew in early fibrosis stages but did not increase in septal or cirrhotic stages and that the portal-bridging fibrosis area appeared as a more accurate tool to assess fibrosis progression than the whole fibrosis area.Modern Pathology advance online publication, 3 January 2014; doi:10.1038/modpathol.2013.225.
    Modern Pathology 01/2014; DOI:10.1038/modpathol.2013.225 · 6.36 Impact Factor
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    ABSTRACT: Background Liver stiffness evaluation (LSE) by Fibroscan is now widely used to assess liver fibrosis in chronic hepatitis C. Liver steatosis is a common lesion in chronic hepatitis C as in other chronic liver diseases, but its influence on LSE remains unclear. We aimed to precisely determine the influence of steatosis on LSE by using quantitative and precise morphometric measurements of liver histology. Methods 650 patients with chronic hepatitis C, liver biopsy, and LSE were included. Liver specimens were evaluated by optical analysis (Metavir F and A, steatosis grading) and by computerized morphometry to determine the area (%, reflecting quantity) and fractal dimension (FD, reflecting architecture) of liver fibrosis and steatosis. Results The relationships between LSE and liver histology were better described using morphometry. LSE median was independently linked to fibrosis (area or FD), steatosis (area or FD), activity (serum AST), and IQR/LSE median. Steatosis area ≥4.0 % induced a 50 % increase in LSE result in patients with fibrosis area <9 %. In patients with IQR/LSE median ≤0.30, the rate of F0/1 patients misclassified as F ≥ 2 by Fibroscan was, respectively for steatosis area <4.0 and ≥4.0 %: 12.6 vs 32.4 % (p = 0.003). Steatosis level did not influence LSE median when fibrosis area was ≥9 %, and consequently did not increase the rate of F ≤ 3 patients misclassified as cirrhotic. Conclusion A precise evaluation of liver histology by computerized morphometry shows that liver stiffness measured by Fibroscan is linked to liver fibrosis, activity, and also steatosis. High level of steatosis induces misevaluation of liver fibrosis by Fibroscan.
    Journal of Gastroenterology 01/2014; DOI:10.1007/s00535-013-0819-9 · 4.02 Impact Factor
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    ABSTRACT: Inflammatory hepatocellular adenomas (IHCAs) are benign liver lesions that can be characterized histologically by the presence of an inflammatory infiltrate and at the molecular level by the overexpression of acute phase inflammatory response genes. Recurrent somatic mutations of the interleukin-6 (IL-6) signal transducer (IL6ST) locus, encoding the critical component of the IL-6 signal transduction machinery gp130, are present in 60% of IHCAs and in a subset (2%) of hepatocellular carcinoma (HCCs). By screening of 256 human hepatic adenoma specimens (the largest genetic analysis of IL6ST performed to date in this setting), we identified 24 distinct somatic IL6ST mutations among 66 mutant adenomas. The functional analysis of nine different gp130 mutants expressed in hepatic cancer cell lines consistently revealed the constitutive and IL-6-independent activation of the JAK/STAT signaling pathway. We further demonstrated that the signaling activity of mutant gp130 in IHCA remains responsive to suppressor of cytokine signaling 3 (SOCS3), a physiological gp130 inhibitor. Specifically, cells expressing a double mutant variant of gp130 with a disrupted SOCS3-binding site at residue 759 (Y186/Y759F) displayed a hyperactivation of signal transducer and activator of transcription 3 (STAT3) as compared with cells expressing the endogenous IHCA-associated Y186 gp130 mutant. Notably, we identified that constitutive signaling via gp130 in IHCA requires the Janus kinase family member JAK1, but not JAK2 or tyrosine kinase 2. In support of this notion, AG490, a tyrosine kinase inhibitor that selectively blocks JAK2, had no effect on gp130 activity. In stark contrast, we showed that ruxolitinib, a JAK1/JAK2-selective tyrosine kinase inhibitor used to treat patients with myelofibrosis, dramatically impaired JAK1-STAT signaling downstream of all IHCA-associated gp130 mutants. In conclusion, our findings provide a rationale for the use of JAK1 inhibitors for the treatment of HCAs expressing mutant gp130 as well as a subset of HCCs that bear similar mutations.
    OncoImmunology 12/2013; 2(12):e27090. DOI:10.4161/onci.27090 · 6.28 Impact Factor
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    ABSTRACT: Objective The aspartate aminotransferase activity (AST)/alanine aminotransferase activity (ALT) ratio is used as liver fibrosis index whereas the reported data are conflicting. In chronic hepatitis C (CHC), reported diagnostic accuracies range from none to good for significant fibrosis and to excellent for cirrhosis. Assuming that AST/ALT increases are mainly due to vitamin B6 defects since pyridoxal phosphate (PLP), active form of B6, acts as coenzyme in transamination reactions, we evaluated the diagnostic accuracy of the AST/ALT ratio using standardized methods for AST and ALT activities, with PLP addition as recommended, in a prospective multicenter cohort of CHC patients. Methods ALT and AST activities were measured using the recommended IFCC methods with addition of pyridoxal 5’-phosphate. We evaluated the AST/ALT ratio for the diagnosis of liver fibrosis or cirrhosis in a cohort of CHC patients included in a multicenter prospective study. A liver biopsy was performed in each patient and reviewed by two independent pathologists in order to determine the fibrosis stage according to Metavir classification which was the reference standard. Results AST/ALT ratio significantly increased with histological stage of liver fibrosis and there was a significant correlation between Metavir fibrosis stage and AST/ALT ratio (r = 0.129, P < 0.0035). The ROC curve analyses showed that the AST/ALT ratio does not discriminate significant fibrosis (F ≥ 2) (AUROC = 0.531) and had only very poor diagnostic accuracies for severe fibrosis (F ≥ 3) (AUROC = 0.584) or cirrhosis (F4) (AUROC = 0.626). Conclusion AST/ALT ratio is not a good and discriminative index of liver fibrosis in CHC when aminotransferase activities are determinate according to the international recommendations.
    Gastroentérologie Clinique et Biologique 11/2013; 37(5):467–472. DOI:10.1016/j.clinre.2013.07.003 · 0.80 Impact Factor
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    ABSTRACT: The prognosis of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA) is mainly linked to tumor recurrence. So far, no tissue biomarker of recurrence has been validated in biopsy samples. We aimed to investigate the prognostic value of tissue biomarkers in HCC biopsy samples of patients treated by RFA. All consecutive naive patients from 3 university hospitals with compensated cirrhosis, early-stage (BCLC 0/A) uninodular HCC treated with RFA, and available tumor biopsy were included. Edmondson's grade, and the expression of cytokeratin 19, glutamine synthase, beta-catenin, epithelial cell adhesion molecule (EpCAM) and endothelial cell-specific molecule 1(ESM-1) were assessed. Main clinical end-points were overall and early recurrence. Statistical analyses were performed using Kaplan Meier, Log-Rang Test and Cox models. 150 patients were included. Recurrence, death or liver transplantation occurred in 85, 51 and 12 patients respectively. Median follow-up was 27 months. ESM-1 expression by HCC stromal endothelial cells was observed in 58 patients (40%) and was associated with higher serum AFP levels, larger tumor, and more frequent expressions of EpCAM and surrogate markers of activation of the Wnt-ßcatenin pathway. The 2 independent predictive factors for overall recurrence were serum AFP (HR 1.11 [1.002; 1.22], p = 0.045), and ESM-1 expression (HR 1.56 [1.004; 2.43], p = 0.048). ESM-1 expression was also an independent predictive factor for early recurrence (HR 1.81 [1.02; 3.21], p = 0.042). ESM-1 expression by stromal endothelial cells, in tumor biopsy samples, has an independent predictive value for early recurrence after RFA.
    Journal of Hepatology 08/2013; DOI:10.1016/j.jhep.2013.07.030 · 9.86 Impact Factor
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    ABSTRACT: We aimed to evaluate the expression and diagnostic value of five immunohistochemical markers (HBME-1, Galectin-3, CK19, CD56 and p63) in a very large series of unequivocal papillary thyroid carcinoma (PTC) cases, including both the classic (CPTC) and the follicular variant (FVPTC). We performed an immunohistochemical analysis on a tissue micro-array of 204 PTCs (98 CPTCs, 90 FVPTCs, and 16 other variants). HBME-1 was the most sensitive marker, staining 95.9% of CPTCs and 81.1% of FVPTCs. CD56, a marker whose expression is reduced or absent in thyroid carcinoma, revealed a negative, "malignant" profile in 93.9% of CPTCs and 73.3% of FVPTCs. Galectin-3, CK19 and p63 were positive in 64.7%, 45.6% and 6.9% of PTCs, respectively. The immunopanel consisting of HBME-1, CD56 and/or CK19 reached the highest sensitivity (95.6%). The co-expression of 2 or more proteins was observed in 88.2% of PTCs, with HBME-1 and CD56 being the most frequent positive association (79.4%). We report a new panel of antibodies consisting of HBME-1, CK19 and CD56 that was found to be highly sensitive for both CPTC and FVPTC. This panel could be recommended as a supplement to the morphological criteria in the diagnosis of difficult FVPTC cases.
    Pathology - Research and Practice 07/2013; DOI:10.1016/j.prp.2013.06.012 · 1.56 Impact Factor
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    ABSTRACT: We aimed to determine the best algorithms for the diagnosis of significant fibrosis in chronic hepatitis C (CHC) patients using all available parameters and tests. We used the database from our study of 507 patients with histologically proven CHC in which fibrosis was evaluated by liver biopsy (Metavir) and tests: Fibrometer®, Fibrotest®, Hepascore®, Apri, ELFG, MP3, Forn's, hyaluronic acid, tissue inhibitor of metalloproteinase-1 (TIMP1), MMP1, collagen IV and when possible Fibroscan™. For the first test we used 90% negative predictive value to exclude patients with F≤1, next an induction algorithm was applied giving the best tests with at least 80% positive predictive value for the diagnosis of F≥2. The algorithms were computed using the R Software C4.5 program to select the best tests and cut-offs. The algorithm was automatically induced without premises on the part of the investigators. We also examined the inter-observer variations after independent review of liver biopsies by two pathologists. A medico-economic analysis compared the screening strategies with liver biopsy. In "intention to diagnose" the best algorithms for F≥2 were Fibrometer ®, Fibrotest®, or Hepascore® in first intention with the ELFG score in second intention for indeterminate cases. The percentage of avoided biopsies varied between 50% (Fibrotest® or Fibrometer®+ELFG) and 51% (Hepascore®+ELFG). In "per-analysis" Fibroscan™+ELFG avoided liver biopsy in 55% of cases. The diagnostic performance of these screening strategies was statistically superior to the usual combinations (Fibrometer® or Fibrotest®+Fibroscan™) and was cost effective. We note that the consensual review of liver biopsies between the two pathologists was mainly in favor of F1 (64-69%). The ELFG test could replace Fibroscan in most currently used algorithms for the diagnosis of significant fibrosis including for those patients for whom Fibroscan™ is unusable.
    PLoS ONE 03/2013; 8(3):e59088. DOI:10.1371/journal.pone.0059088 · 3.53 Impact Factor
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    ABSTRACT: Liver fibrosis, now assessed by liver biopsy or using non-invasive methods, might be different in chronic hepatitis B (CHB) and chronic hepatitis C (CHC). To compare histological amount and pattern of fibrosis in CHB and CHC. Sixty CHB and sixty CHC biopsies from naïve patients, standardized for the spectrum of Metavir fibrosis stages, were analysed for (1) semi-quantitative Metavir activity, steatosis, perisinusoidal fibrosis, alpha-smooth muscle actin immunoreactivity, (2) quantitative morphometry of total and perisinusoidal fibrosis ratio (FR and PFR). Biopsy quality, activity, steatosis, Fibrotest(®) values were not different between the two groups. Correlation between FR and fibrosis stage was stronger in CHB (r = 0.90) than CHC (r = 0.81). Mean FR was 1.5-fold higher in CHC than CHB for early fibrosis stages (F ≤ 2, P = 0.001), with higher PFR in CHC for F0 (P = 0.001), F1 (P = 0.08) and F2 (P = 0.004). Hepatic stellate cell activation index was also higher in CHC than in CHB (P = 0.007). Diagnosis performance of FR for significant fibrosis was not statistically different in CHB than CHC (AUROC 0.92 and 0.87 respectively), but cut-offs optimizing sensitivity and specificity were higher in CHC and their extrapolation to CHB led to 10% decrease in sensitivity. In F ≤ 2 patients, correlation between FR and Fibrotest(®) was only significant in CHC. As compared to CHB, amount of fibrosis is greater in CHC for F ≤ 2 patients, mainly because of higher perisinusoidal fibrosis. These data illustrate difficulty to assess early fibrosis stages by non-invasive methods, and support the need for specific cut-offs in CHB.
    Liver international: official journal of the International Association for the Study of the Liver 03/2013; 33(3):428-38. DOI:10.1111/liv.12092 · 4.41 Impact Factor
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    ABSTRACT: BACKGROUND: Liver stiffness evaluation (LSE) is usually considered as reliable when it fulfills all the following criteria: =10 valid measurements, ≥60% success rate, and IQR/median ratio (IQR/M) ≤0.30. However, such reliable LSE have never been shown to be more accurate than unreliable LSE. Thus, we aimed to evaluate the relevance of the usual definition for LSE reliability, and to improve reliability by using diagnostic accuracy as a primary outcome in a large population. METHODS: 1165 patients with chronic liver disease from 19 French centers were included. All patients had liver biopsy and LSE. RESULTS: 75.7% of LSE were reliable according to the usual definition. However, these reliable LSE were not significantly more accurate than unreliable LSE with, respectively: 85.8% vs 81.5% well-classified patients for the diagnosis of cirrhosis (p=0.082). In multivariate analyses with different diagnostic targets, LSE median and IQR/M were independent predictors of fibrosis staging, with no significant influence of =10 valid measurements or LSE success rate. These two reliability criteria determined 3 LSE groups: "very reliable" (IQR/M ≤0.10), "reliable" (0.10 <IQR/M ≤0.30, or IQR/M >0.30 with LSE median <7.1 kPa), and "poorly reliable" (IQR/M >0.30 with LSE median ≥7.1 kPa). The rates of well-classified patients for the diagnosis of cirrhosis were, respectively: 90.4%, 85.8%, and 69.5% (p<10(-3) ). According to these new reliability criteria, 9.1% of LSE were "poorly reliable" (versus 24.3% unreliable LSE with the usual definition, p<10(-3) ), 74.3% were "reliable", and 16.6% were "very reliable". CONCLUSION: The usual definition for LSE reliability is not relevant. LSE reliability depends on IQR/M according to liver stiffness median level, defining thus three reliability categories: "very reliable", "reliable", and "poorly reliable" LSE. (HEPATOLOGY 2012.).
    Hepatology 03/2013; 57(3). DOI:10.1002/hep.25993 · 11.19 Impact Factor
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    ABSTRACT: Temozolomide (TMZ) has been proposed as a therapeutic option in aggressive pituitary tumors. Among the published cases, GH expressing tumors were rare. We describe a patient with initially benign silent GH adenoma that transformed into an aggressive GH secreting tumor resistant to usual therapy. MGMT expression was high and the MGMT promoter was unmethylated. Before this aggressive course, patient received three cycles of TMZ; no response was observed. Four cases of GH aggressive tumor treated by TMZ have been reported. Response to TMZ was observed in one of these four patients. Predictive factors of failure of TMZ remain unclear.
    Cancer Investigation 03/2013; 31(3):190-6. DOI:10.3109/07357907.2013.775293 · 2.24 Impact Factor
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    ABSTRACT: Liver cirrhosis is a recognized risk factor for intrahepatic cholangiocarcinoma (I-CCa). Small I-CCa nodules might be undiagnosed or misdiagnosed as hepatocellular carcinoma (HCC) in the context of liver cirrhosis. The aim of this study was to determine the prevalence and clinical impact of undetected I-CCa in liver explants of adult cirrhotic patients undergoing liver transplantation (LT). From December 1985 to November 2008, a first LT was performed in 993 adult cirrhotic patients in three French academic Hospitals. All liver explants were analyzed for the presence of nodules. The diagnosis of HCC was made in 331 cases (33.3% of the patients). Similarly, an I-CCa was identified in 10 (1%) patients, with a mean size of 31 ± 17 mm. The mean age at transplantation was 58.8 yr (range 45 - 66), and all the patients were men. The mean follow-up after LT was 33 months (range 4-52). Post-transplant tumor recurrence was observed in five patients (50%), after a mean delay of 10 months. All five patients died. Malignant recurrence was associated with the presence of venous emboli on liver explants. Our results suggest that unrecognized I-CCa complicating liver cirrhosis is a rare entity, associated with high risk of recurrence and poor prognosis.
    Clinical Transplantation 02/2013; 27(3). DOI:10.1111/ctr.12108 · 1.49 Impact Factor
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    ABSTRACT: Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.
    Acta Neuropathologica 02/2013; 126(1). DOI:10.1007/s00401-013-1084-y · 9.78 Impact Factor
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    ABSTRACT: Phenotypic identification of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) subtypes using immunohistochemical markers has been developed from their molecular characteristics. Our objective was to evaluate the sensitivity of these markers in the definitive diagnosis of these lesions by core needle biopsies. A total of 239 needle biopsies paired with their surgical resection specimen (group A) or without an associated resection specimen (group B) were reviewed. Using a step-by-step algorithm after standard staining, appropriate immunostaining analyses were performed to determine the certainty of diagnosis of FNH, HNF1α-inactivated HCA, inflammatory HCA, β-catenin-activated HCA, or unclassified HCA. The diagnosis of FNH was certain or probable on routine stains in 53% of needle biopsies of group A, whereas after glutamine synthetase staining, the diagnosis was certain in 86.7% as compared with 100% on the corresponding surgical specimen (P=0.04). In needle biopsies of group A, the diagnosis of HCA was certain on routine stains in 58.6% as compared with 94.3% on surgical specimens. After specific immunostaining, diagnosis was established on biopsies with 74.3% certainty, including all HCA subtypes, with similar distribution in surgical specimens. For each "certain diagnosis" paired diagnostic test (biopsy and surgical specimen), a positive correlation was observed (P<0.001). No significant difference was observed between groups A and B for FNH (P=0.714) or for HCA subtypes (P=0.750). Compared with surgical specimens, immunohistochemical analysis performed on biopsies allowed the discrimination of FNH from HCA and the identification of HCA subtypes with good performance.
    The American journal of surgical pathology 10/2012; 36(11):1691-1699. DOI:10.1097/PAS.0b013e3182653ece · 4.59 Impact Factor
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    ABSTRACT: BACKGROUND: Noninvasive methods for liver fibrosis evaluation in chronic liver diseases have been recently developed, i.e. transient elastography (Fibroscan™) and blood tests (Fibrometer®, Fibrotest®, and Hepascore®). In this study, we aimed to design a new score in chronic hepatitis C (CHC) by selecting blood markers in a large panel and we compared its diagnostic performance with those of other noninvasive methods. METHODS: Sixteen blood tests were performed in 306 untreated CHC patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar) using METAVIR histological fibrosis stage as reference. The new score was constructed by non linear regression using the most accurate biomarkers. RESULTS: Five markers (alpha-2-macroglobulin, apolipoprotein-A1, AST, collagen IV and osteoprotegerin) were included in the new function called Coopscore©. Using the Obuchowski Index, Coopscore© shows higher diagnostic performances than for Fibrometer®, Fibrotest®, Hepascore® and Fibroscan™ in CHC. Association between Fibroscan™ and Coopscore© might avoid 68% of liver biopsies for the diagnosis of significant fibrosis. CONCLUSION: Coopscore© provides higher accuracy than other noninvasive methods for the diagnosis of liver fibrosis in CHC. The association of Coopscore© with Fibroscan™ increases its predictive value.
    Clinica chimica acta; international journal of clinical chemistry 09/2012; 415. DOI:10.1016/j.cca.2012.09.020 · 2.54 Impact Factor
  • Annales d Endocrinologie 09/2012; 73(4):270. DOI:10.1016/j.ando.2012.07.110 · 0.66 Impact Factor
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    ABSTRACT: The single nucleotide polymorphisms (rs12979860), near the IL28B gene, is correlated with a sustained virological response (SVR) in Hepatitis C Virus (HCV) infected patients treated with Pegylated Interferon-α combined with Ribavirin (1,2). However, the association of rs12979860 polymorphism with immune function of the liver, the site of HCV production, and the mechanism of SVR remain still undefined.Methods Patients chronically HCV-infected patients were genotyped for rs12979860 defining C/T polymorphism. C allele is associated to SVR. Liver samples were collected from the needle biopsy achieved for the diagnosis prior any treatment. Single cell suspensions were prepared by mechanical disruption. Liver lymphocytes (T, Treg, NK and NKT) were identified by flow cytometry for the expression of CD45, CD3, CD4, CD8, CD56 and FoxP3 as markers and CD107a for degranulation activity. Expression of CD8β, FoxP3, IL10 and HPRT genes was measured by PCR. Immunohistochemistry were performed on in paraffin sections for the detection of CD8 and FoxP3. Statistical analysis wwas done with Mann–Whitney U test and Wilcoxon matched-t test.ResultsLymphocytes from 52 fresh liver biopsies displayed similar distributions of T (CD3), NKT (CD3, CD56) and NK (CD56) among CD45 cells by flow cytometry multi parametric analysis, whatever the IL28B genotype of the patients. Strikingly, higher degranulation activity, revealed by CD107a surface expression, was observed in T (p = 0.000), NKT (p = 0.002) and NK cells (p = 0.015) of patients with CC genotype (n = 17) compared to patients with CT or TT genotypes (n = 35); patients with CC genotype displayed two fold higher degranulation activity than patients with CT genotype in T (p = 0.001), NKT (p = 0.002) and NK cells (p = 0.011); no significant difference was observed between patients with CT and TT genotypes. Sections of liver from 19 patients showed the frequency of CD4-FoxP3 lymphocytes two fold higher (p = 0.004) in patients with CC genotype (n = 11) as compared to patients with CT genotype (n = 8) supporting the presence of Treg. Previous study demonstrated that the ratio between the number of CD8 cells and FoxP3 cells in parenchymatous necro-inflammatory areas is maintained in the early stage of the chronic hepatitis (3). This is found only in patients with CC genotype, whereas this ratio is reduced in patients with CT genotype due to lower number of FoxP3 cells. Transcriptional analyses confirmed these data and further showed two strong correlations between: one between FoxP3 and CD8β, another between FoxP3 and IL-10 expressions in patients with CC genotype.Conclusion Collectively these data provide new insights into the role of IL28B polymorphism related to SVR in treatment of HCV infected patients. CC genotype, which is linked to good response, is associated to higher efficiency of effector lymphocytes (T, NK and NKT) of the liver. The liver immune response appears tightly regulated as suggested by the links between CD8 cells and CD4-FoxP3 cells, and between IL10 and FoxP3 gene expression.
    Cytokine 09/2012; 59(3):562. DOI:10.1016/j.cyto.2012.06.226 · 2.87 Impact Factor
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    ABSTRACT: The Weiss score is the reference method to distinguish between a benign and a malignant adrenocortical tumor (ACT). A program was initiated to improve the reproducibility of the pathologic diagnosis of ACTs in France through the National INCa-COMETE Network. Twelve pathologists from all Reference Centers of the Network analyzed 50 selected ACTs using a web-based virtual microscopy approach in a blind design, allowing to determine the intraobserver and interobserver reproducibilities of the Weiss system. All ACTs were read twice in random order before and after a coaching meeting organized to harmonize and improve analyses and create an online tutorial. The validity of the virtual approach was first established by comparing the 2 consensuses (virtual and microscopic) obtained for each tumor by 3 pathologists who performed the 2 approaches in a blinded manner. For the "dichotomized Weiss score" (separating malignant ≥3 from benign ≤2 tumors) interobserver reproducibility was "substantial" at the first "virtual" reading (κ = 0.70) and increased at the second "virtual" reading (κ = 0.75). In parallel, 7 of the 9 items of the Weiss system showed improvement. The diagnostic accuracy of the observers as a group, using the modal group score approach, showed an improved sensitivity from 86% to 95% for the diagnosis of malignant ACTs. We show the validity of the virtual microscopy approach and that the program improved the practice of the Weiss system reading and therefore the diagnosis of ACT. This tool can now be extended for other research and/or routine purposes in this rare cancer.
    The American journal of surgical pathology 08/2012; 36(8):1194-201. DOI:10.1097/PAS.0b013e31825a6308 · 4.59 Impact Factor

Publication Stats

2k Citations
500.70 Total Impact Points


  • 2009–2014
    • University Joseph Fourier - Grenoble 1
      Grenoble, Rhône-Alpes, France
    • French Institute of Health and Medical Research
      • Centre d’Immunologie de Marseille Luminy CIML U1104
      Paris, Ile-de-France, France
  • 2003–2014
    • University of Grenoble
      Grenoble, Rhône-Alpes, France
    • Università degli Studi di Modena e Reggio Emilia
      Modène, Emilia-Romagna, Italy
  • 2002–2013
    • Centre Hospitalier Universitaire de Grenoble
      • Département d'Anatomie et Cytologie Pathologiques
      Grenoble, Rhône-Alpes, France
  • 2012
    • UNIT
      Miami, Florida, United States
  • 2007–2010
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2008
    • Centre Hospitalier Universitaire d'Angers
      • Service d'hépatologie gastro-entérologie
      Angers, Pays de la Loire, France
  • 2004–2006
    • Laboratoire d'Informatique de Grenoble
      Grenoble, Rhône-Alpes, France
  • 2001
    • Università degli Studi di Torino
      Torino, Piedmont, Italy