Reliability Criteria of Two-Dimensional Shear Wave Elastography: Analysis of 4277 Measurements in 788 Patients.

BACKGROUND & AIMS: Two-dimensional shear wave elastography (2D-SWE) is an accurate method for the non-invasive evaluation of liver fibrosis. We aimed to determine the reliability criteria and the number of necessary reliable measurements for 2D-SWE. METHODS: 788 patients with chronic liver disease underwent liver biopsy and 2D-SWE examination in three centers. The 4277 2D-SWE measurements performed were 2:1 randomly divided into derivation (n = 2851) and validation (n = 1426) sets. Reliability criteria for a 2D-SWE measurement were defined in the derivation set from the intrinsic characteristics given by the device (mean liver stiffness, standard deviation, diameter of the region of interest), with further evaluation in the validation set. RESULTS: In the whole population of 4277 measurements, AUROC for bridging fibrosis was 0.825 ± 0.006 and AUROC for cirrhosis was 0.880 ± 0.006. Mean stiffness and coefficient of variation (CV) were independent predictors of bridging fibrosis or cirrhosis. From these two parameters, new criteria were derived to define a reliable 2D-SWE measurement: stiffness <8.8 kPa, or stiffness between 8.8-11.9 kPa with CV <0.25, or stiffness ≥12.0 kPa with CV <0.10. In the validation set, AUROC for bridging fibrosis was 0.830 ± 0.013 in reliable measurements vs 0.667 ± 0.031 in unreliable measurements (P < .001). AUROC for cirrhosis was 0.918±0.014 vs 0.714 ± 0.027, respectively (P < .001). The best diagnostic accuracy for a 2D-SWE examination was achieved from three reliable measurements. CONCLUSIONS: Reliability of a 2D-SWE measurement relies on the coefficient of variation and the liver stiffness level. A 2D-SWE examination should include three reliable measurements according to our new criteria.

Sequential mutational evaluation of CALR -mutated myeloproliferative neoplasms with thrombocytosis reveals an association between CALR allele burden evolution and disease progression.

In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR-mutated cases. Additional mutations found by next-generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR-mutated patients. We performed a molecular evaluation combining next-generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow-up in a cohort of 45 patients with CALR-mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1-like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow-up, independently of additional mutations and WHO2016-reviewed diagnosis. Patients with disease progression at the time of follow-up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring.

Expression of programmed death-ligand 1 (PD-L1) in human pituitary neuroendocrine tumor.

OBJECTIVE: To explore the programmed death-ligand 1 (PD-L1) expression in varied subtypes of pituitary neuroendocrine tumors with assessment of their clinical behavior at diagnosis and follow-up. METHODS: We conducted a retrospective monocentric study, including all patients operated in the Academic Hospital of Angers (France) for a pituitary neuroendocrine tumor between 2012 and 2018. PDL-1 immunostaining was performed using a European Conformity-In Vitro Diagnostic-labeled anti-PDL1 antibody (clone 22C3). PD-L1 immunostaining was evaluated as the percentage of tumor cells showing positive membrane staining, into four grades: grade 0 = < 1%, grade 1 = 1 to 5%, grade 2 = 6 to 49% and grade 3 = ≥ 50%. PD-L1 expression was compared with tumor features (secretion, proliferation, invasion) and outcome. RESULTS: The study included 139 pituitary neuroendocrine tumors, including 84 (60%) nonfunctioning adenomas. Twenty-five pituitary neuroendocrine tumors were PD-L1 positive (18%), including 3 grade 3, 8 grade 2 and 14 grade 1. PD-L1 expression was not different between functioning and nonfunctioning adenomas (p = 0.26). Among 16 tumors with proliferative markers (Ki-67 ≥ 3% and p53 positive), only one was PD-L1 positive. CONCLUSION: In our series, PD-L1 was expressed in a rather small proportion of PitNET (18%), and this immune marker was not associated with any biological characteristic or behavior of the pituitary tumors. Thus, PD-L1 staining may be necessary before considering PD-L1 blockage in pituitary neuroendocrine tumors, in case of therapeutic impasse.

Histopathological Diagnosis of Prosthetic Joint Infection: Does a Threshold of 23 Neutrophils Do Better than Classification of the Periprosthetic Membrane in a Prospective Multicenter Study?

No gold standard exists for histopathological diagnosis of a prosthetic joint infection (PJI). The historical criterion considers the presence of neutrophil infiltration upon examination of periprosthetic tissue. Morawietz et al. proposed a classification of periprosthetic membranes (Morawietz et al., Clin Pathol 59:591-597, 2006, https://doi.org/10.1136/jcp.2005.027458) and a more recently described classification with a new cutoff value of 23 neutrophils in 10 high-power fields (Morawietz et al., Histopathology 54:847-853, 2009. https://doi.org/10.1111/j.1365-2559.2009.03313.x). We performed a multicenter prospective study, which compared both methods for the diagnosis of PJI. All suspicions of PJI (n = 264) between December 2010 and March 2012 in seven centers were prospectively included. Five perioperative specimens were collected per patient for cultures, and one was collected for histology. Diagnosis of PJI was made according to the Infectious Diseases Society of America (IDSA) guidelines. Histopathological analysis classified the patients according to the threshold of 23 neutrophils and according to the classification of Morawietz. Performances of both methods were compared by using clinical and/or bacteriological criteria as the gold standard. Among 264 patients with suspected PJI, a diagnosis of infection was confirmed in 215 and unconfirmed in 49 patients. Histopathological analysis was available for 150 confirmed PJI and 40 unconfirmed PJI cases. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 78.7%, 90.0%, 96.7%, 52.9%, and 81.1%, respectively, for the Morawietz classification, and 82.0%, 90.0%, 96.9%, 57.1%, and 83.7%, respectively, for the 23-neutrophil threshold. The new algorithm using a threshold of 23 neutrophils can be proposed as a new gold standard for the histopathological diagnosis of PJI.

Impact of front line relative dose intensity for methotrexate and comorbidities in immunocompetent elderly patients with primary central nervous system lymphoma.

Primary central nervous system lymphomas (PCNSL) are non-Hodgkin lymphomas strictly localized to the CNS, occurring mainly in elderly patients with comorbidities. Current treatment in fit patients relies on high-dose methotrexate and high-dose cytarabine. The aim of this study was to evaluate the efficacy and feasibility of this treatment in elderly patients and to assess potential prognostic factors associated with survival. We conducted a retrospective study in two centers between January 2008 and September 2015 including 35 elderly immunocompetent patients who received first-line treatment with high-dose methotrexate. With a median follow-up of 19.8 months (range: 1.7-73.4 months), median overall survival (OS) was 39.5 months (95% confidence interval (95% CI): 18.3-60.7) and median progression-free survival (PFS) was 25.8 months (95% CI: 5.2-46.4). In univariate analysis, administration of high-dose cytarabine and achieving a relative dose intensity for methotrexate > 75% were associated with increased OS (p = 0.006 and p = 0.003, respectively) and PFS (p = 0.003 and p = 0.04, respectively) whereas comorbidities, defined by a CIRS-G score ≥ 8, were associated with decreased OS and PFS (p = 0.02 and p = 0.04, respectively). A high MSKCC score was associated with decreased OS (p = 0.02). In multivariate analysis, administration of high-dose cytarabine was associated with increased OS and PFS (p = 0.02 and p = 0.007, respectively). Comorbidities and relative dose intensity for methotrexate are important for the prognosis of elderly patients with PCNSL. These results must be confirmed in prospective trials.

How Did We Obtain Complete Remission in Patients Who Had Metastatic Renal Cancer in the Era of Targeted Therapies?

BACKGROUND: The management of metastatic renal cell carcinoma (mRCC) has been transformed by the use of targeted therapies, ablative therapies and improved surgical techniques. The objective of this study was to identify therapeutic strategies that resulted in complete remission (CR) and to assess survival of patients in CR. METHODS: In a prospective database, we included all patients treated for mRCC at a university hospital between 2007 and 2015. CR was defined as the absence of metastasis after a full-body computed tomographic scan. RESULTS: We treated 77 patients with mRCC and experienced a CR in 22 (29 %) patients. Patients in CR had, respectively, synchronous and metachronous metastases in 7 (32 %) and 15 (68 %) cases and unique and multiple metastases in 4 (18 %) and 18 (82 %) cases. All patients were treated with cytoreductive nephrectomy and 21 (96 %) had metastasectomy or percutaneous ablation of their metastases. One patient had a CR after systemic treatment with sunitinib. After a median (range) follow-up since metastatic diagnosis of 35 (1-89) months, 12 patients (55 %) had disease recurrence. The median (range) duration of CR before recurrence was 14 (1-39) months. After recurrence, a new CR was obtained in 7 patients (58 %). At the end of follow-up, 16 patients (73 %) were still in CR, 5 (23 %) were undergoing medical treatment, and 1 patient died during the postoperative course. CONCLUSIONS: In the era of targeted-therapies, CRs were obtained with multimodal treatment of metastatic kidney cancer. All patients in CR had a nephrectomy and almost all of them had multiple metastasectomies.

Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: NAFLD is highly prevalent but only a small subset of patients develop advanced liver fibrosis with impaired liver-related prognosis. We aimed to compare blood fibrosis tests and liver stiffness measurement (LSM) by FibroScan for the diagnosis of liver fibrosis and the evaluation of prognosis in NAFLD. METHODS: Diagnostic accuracy was evaluated in a cross-sectional study including 452 NAFLD patients with liver biopsy (NASH-CRN fibrosis stage), LSM, and eight blood fibrosis tests (BARD, NAFLD fibrosis score, FibroMeter(NAFLD), aspartate aminotransferase to platelet ratio index (APRI), FIB4, FibroTest, Hepascore, FibroMeter(V2G)). Prognostic accuracy was evaluated in a longitudinal study including 360 NAFLD patients. RESULTS: LSM and FibroMeter(V2G) were the two best-performing tests in the cross-sectional study: AUROCs for advanced fibrosis (F3/4) were, respectively, 0.831±0.019 and 0.817±0.020 (p⩽0.041 vs. other tests); rates of patients with ⩾90% negative/positive predictive values for F3/4 were 56.4% and 46.7% (p<0.001 vs. other tests); Obuchowski indexes were 0.834±0.014 and 0.798±0.016 (p⩽0.036 vs. other tests). Two fibrosis classifications were developed to precisely estimate the histological fibrosis stage from LSM or FibroMeter(V2G) results without liver biopsy (diagnostic accuracy, respectively: 80.8% vs. 77.4%, p=0.190). Kaplan-Meier curves in the longitudinal study showed that both classifications categorised NAFLD patients into subgroups with significantly different prognoses (p<0.001): the higher was the class of the fibrosis classification, the worse was the prognosis. CONCLUSIONS: LSM and FibroMeter(V2G) were the most accurate of nine evaluated tests for the non-invasive diagnosis of liver fibrosis in NAFLD. LSM and FibroMeter(V2G) fibrosis classifications help physicians estimate both fibrosis stage and patient prognosis in clinical practice. LAY SUMMARY: The amount of liver fibrosis is the main determinant of the liver-related prognosis in patients with non-alcoholic fatty liver disease (NAFLD). We evaluated eight blood tests and FibroScan in a cross-sectional diagnostic study and found that FibroScan and the blood test FibroMeter(V2G) were the two most accurate tests for the non-invasive evaluation of liver fibrosis in NAFLD. A longitudinal prognostic study showed these two tests initially developed for the diagnosis are also prognostic markers as they allow for the stratification of NAFLD patients in several subgroups with significantly different prognosis.

[Solitary fibrous tumors and hemangiopericytomas of the meninges: Immunophenotype and histoprognosis in a series of 17 cases]. / Tumeurs fibreuses solitaires et hémangiopéricytomes des méninges : immunophénotype et évaluation du grade histopronostique dans 17 cas.

INTRODUCTION: The 2007 World Health Organization (WHO) classification of tumors of the central nervous system distinguishes meningeal hemangiopericytomas (HPC) from solitary fibrous tumors (TFS). In the WHO classification of tumors of soft tissue and bone, those neoplasms are no longer separate entities since the discovery in 2013 of a common oncogenic event, i.e. the NAB2-STAT6 gene fusion. A shared histopronostic grading system, called "Marseille grading system", was recently proposed, based on hypercellularity, mitotic count and necrosis. We evaluated the immunophenotype and histoprognosis in a retrospective cohort of intracranial HPC and TFS. METHODS: Fifteen initial tumors and 2 recurrences were evaluated by immunohistochemistry for STAT6, CD34, EMA, progesterone receptors and Ki67. The pronostic value of the WHO and the Marseille grading systems was tested on 12 patients with clinical follow-up. RESULTS: Initial tumors were 11 HPC and 4 SFT. STAT6 and CD34 were expressed in 16/17 tumors, EMA and progesterone receptors in 2 and 5 cases, respectively. The Ki67 labelling index was 6.25% in HPC and 3% in SFT. Half of the tumors recurred between 2 years and 9 years after initial diagnosis (mean time 5 years). No statistical difference in the risk of recurrence was associated with either grade (WHO or Marseille), in this small cohort. CONCLUSION: The diagnosis of HPC and TFS is facilitated by the almost constant immuno-expression of STAT6, and this justifies their common classification. The high rate of recurrence implies a very long-term follow-up because the current grading systems do not accurately predict the individual risk.

Safe lipid nanocapsule-based gel technology to target lymph nodes and combat mediastinal metastases from an orthotopic non-small-cell lung cancer model in SCID-CB17 mice.

The purpose of this study is the assessment of gel technology based on a lauroyl derivative of gemcitabine encapsulated in lipid nanocapsules delivered subcutaneously or intravenously after dilution to (i) target lymph nodes, (ii) induce less systemic toxicity and (iii) combat mediastinal metastases from an orthotopic model of human, squamous, non-small-cell lung cancer Ma44-3 cells implanted in severe combined immunodeficiency mice. The gel technology mainly targeted lymph nodes as revealed by the biodistribution study. Moreover, the gel technology induced no significant myelosuppression (platelet count) in comparison with the control saline group, unlike the conventional intravenous gemcitabine hydrochloride treated group (P<0.05). Besides, the gel technology, delivered subcutaneously twice a week, was able to combat locally mediastinal metastases from the orthotopic lung tumor and to significantly delay death (P<0.05) as was the diluted gel technology delivered intravenously three times a week. FROM THE CLINICAL EDITOR: Lung cancer is one of the leading causes of mortality worldwide. A significant proportion of patients with this disease have lymph node metastasis. In this study, the authors investigated the use of lipid nanocapsules, loaded with the lipophilic pro-drug gemcitabine for targeting tumors in lymph nodes after subcutaneous injection. This delivery method was shown to be effective in controlling tumor progression and may be useful in future clinical use.

Quantification of portal-bridging fibrosis area more accurately reflects fibrosis stage and liver stiffness than whole fibrosis or perisinusoidal fibrosis areas in chronic hepatitis C.

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.

Determination of reliability criteria for liver stiffness evaluation by transient elastography.

UNLABELLED: Liver stiffness evaluation (LSE) is usually considered as reliable when it fulfills all the following criteria: ≥10 valid measurements, ≥60% success rate, and interquartile range / 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. 1,165 patients with chronic liver disease from 19 French centers were included. All patients had liver biopsy and LSE. 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% versus 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 three 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 2013).

SMARCB1/INI1 inactivation in renal medullary carcinoma.

AIMS: Renal medullary carcinoma (RMC), a rare and highly aggressive tumour which occurs in patients with sickle-cell disease, shares many clinicopathological features with collecting duct carcinoma (CDC). The molecular mechanisms underlying RMC and CDC are mainly unknown, and there is ongoing debate about their status as distinct entities. Loss of expression of SMARCB1/INI1, a chromatin remodelling regulator and repressor of cyclin D1 transcription, has been reported recently in RMC. The aim of our study was to investigate if such loss of expression is specific for RMC. SMARCB1/INI1 genetic alterations and cyclin D1 expression were also studied. METHODS AND RESULTS: Using immunochemistry, neoplastic cells showed complete loss of SMARCB1/INI1 expression in all six cases of RMC but in only one of 22 cases of CDC. In two RMC cases investigated, comparative genomic hybridization demonstrated complete loss of one SMARCB1/INI1 allele, with no other genomic imbalances, and no mutations were found on the remaining allele. Cyclin D1 was expressed in all RMCs, suggesting that SMARCB1/INI1 inactivation may result in increased cyclin D1 transcription. CONCLUSIONS: The specific SMARCB1/INI1 inactivation observed in RMCs suggests that RMC and CDC are different entities.

Second-line treatment and prognostic factors in neuroendocrine carcinoma: the RBNEC study.

Neuroendocrine carcinomas (NEC) are aggressive malignant diseases. Etoposide-based rechallenge (EBR) and the prognostic role of RB transcriptional corepressor 1 (RB1) status in second-line chemotherapy (2L) have not been studied. The objectives of this study were to report the results of 2L including EBR as well as prognostic factors in a national retrospective multicentre study. NEC patients treated with 2L and further, with tissue samples available, were included. RB1 status and morphological classification were reviewed centrally. Among the 121 NEC patients (40% female, median age 61 years) included, there were 73 small-cell NEC (60%), 34 large-cell NEC (28%) and 14 NEC (not otherwise specified, 12%). Primary sites were lung (39%), gastroenteropancreatic (36%), other (13%) and unknown (12%). Median Ki-67 index was 80%. Median progression-free survival (PFS) and overall survival (OS) under 2L were 2.1 and 6.2 months, respectively. No difference was observed between patients who received an 'adenocarcinoma-like' or a 'neuroendocrine-like' 2L or according to the RB1 status. Thoracic NEC primary was the only adverse prognostic factor for OS. EBR, administered to 31 patients, resulted in a 62% disease control rate with a median PFS and OS of 3.2 and 11.7 months, respectively. In the 94 patients with a relapse-free interval of ≥3 months after first-line platinum-etoposide chemotherapy, the median OS was 12 months in patients who received EBR as compared to 5.9 months in patients who did not (P = 0.043). EBR could be the best 2L option for patient with initial response to first-line platinum-etoposide lasting at least 3 months. RB1 status does not provide prognostic information in this setting.

A new combination of blood test and fibroscan for accurate non-invasive diagnosis of liver fibrosis stages in chronic hepatitis C.

OBJECTIVES: Precise evaluation of the level of liver fibrosis is recommended in patients with chronic hepatitis C (CHC). Blood fibrosis tests and Fibroscan are now widely used for the non-invasive diagnosis of liver fibrosis. Detailed fibrosis stage classifications have been developed to provide an estimation of the liver fibrosis stage from the results of these non-invasive tests. Our aim was to develop a new and more accurate fibrosis stage classification by using new scores combining non-invasive fibrosis tests. METHODS: In all, 729 patients with CHC (exploratory set: 349; validation set: 380) had liver biopsy for Metavir fibrosis (F) staging, and 6 fibrosis tests: Fibroscan, Fibrotest, FibroMeter, Hepascore, FIB-4, APRI. RESULTS: Exploratory set: Fibroscan and FibroMeter were the independent predictors of different diagnostic targets of liver fibrosis. New fibrosis indexes combining FibroMeter and Fibroscan were thus developed for the diagnosis of clinically significant fibrosis (CSF-index) or severe fibrosis (SF-index). The association of CSF- and SF-indexes provided a new fibrosis stage classification (CSF/SF classification): F0/1, F1/2, F2 ± 1, F2/3, F3 ± 1, F4. Validation set: CSF/SF classification had a high diagnostic accuracy (85.8% well-classified patients), significantly higher than the diagnostic accuracies of FibroMeter (69.7%, P<0.001), Fibroscan (63.3%, P<0.001), or Fibrotest (43.9%, P<0.001) classifications. CONCLUSIONS: The association of new fibrosis indexes combining FibroMeter and Fibroscan provides a new fibrosis stage classification. This classification is significantly more accurate than Fibrotest, FibroMeter, or Fibroscan classifications, and improves the accuracy of the non-invasive diagnosis of liver fibrosis stages to 86% without any liver biopsy.

Comparison of accuracy of fibrosis degree classifications by liver biopsy and non-invasive tests in chronic hepatitis C.

BACKGROUND: Non-invasive tests have been constructed and evaluated mainly for binary diagnoses such as significant fibrosis. Recently, detailed fibrosis classifications for several non-invasive tests have been developed, but their accuracy has not been thoroughly evaluated in comparison to liver biopsy, especially in clinical practice and for Fibroscan. Therefore, the main aim of the present study was to evaluate the accuracy of detailed fibrosis classifications available for non-invasive tests and liver biopsy. The secondary aim was to validate these accuracies in independent populations. METHODS: Four HCV populations provided 2,068 patients with liver biopsy, four different pathologist skill-levels and non-invasive tests. Results were expressed as percentages of correctly classified patients. RESULTS: In population #1 including 205 patients and comparing liver biopsy (reference: consensus reading by two experts) and blood tests, Metavir fibrosis (FM) stage accuracy was 64.4% in local pathologists vs. 82.2% (p < 10-3) in single expert pathologist. Significant discrepancy (≥ 2FM vs reference histological result) rates were: Fibrotest: 17.2%, FibroMeter2G: 5.6%, local pathologists: 4.9%, FibroMeter3G: 0.5%, expert pathologist: 0% (p < 10-3). In population #2 including 1,056 patients and comparing blood tests, the discrepancy scores, taking into account the error magnitude, of detailed fibrosis classification were significantly different between FibroMeter2G (0.30 ± 0.55) and FibroMeter3G (0.14 ± 0.37, p < 10-3) or Fibrotest (0.84 ± 0.80, p < 10-3). In population #3 (and #4) including 458 (359) patients and comparing blood tests and Fibroscan, accuracies of detailed fibrosis classification were, respectively: Fibrotest: 42.5% (33.5%), Fibroscan: 64.9% (50.7%), FibroMeter2G: 68.7% (68.2%), FibroMeter3G: 77.1% (83.4%), p < 10-3 (p < 10-3). Significant discrepancy (≥ 2 FM) rates were, respectively: Fibrotest: 21.3% (22.2%), Fibroscan: 12.9% (12.3%), FibroMeter2G: 5.7% (6.0%), FibroMeter3G: 0.9% (0.9%), p < 10-3 (p < 10-3). CONCLUSIONS: The accuracy in detailed fibrosis classification of the best-performing blood test outperforms liver biopsy read by a local pathologist, i.e., in clinical practice; however, the classification precision is apparently lesser. This detailed classification accuracy is much lower than that of significant fibrosis with Fibroscan and even Fibrotest but higher with FibroMeter3G. FibroMeter classification accuracy was significantly higher than those of other non-invasive tests. Finally, for hepatitis C evaluation in clinical practice, fibrosis degree can be evaluated using an accurate blood test.