Liver transarterial chemoembolization and sunitinib for unresectable hepatocellular carcinoma: Results of the PRODIGE 16 study.

BACKGROUND: Trans-arterial chemoembolization (TACE) is one first-line option therapy for patients with hepatocellular carcinoma (HCC) not suitable for surgical resection. AIMS: We evaluated the effects of sunitinib plus doxorubicin-TACE on bleeding or liver failure. METHODS: Seventy-eight patients with HCC were included in this randomized, double-blind study. They received one to three TACE plus either sunitinib or placebo four weeks out of six for one year. The occurrence of severe bleeding or liver failure was assessed during the week after the TACE. The safety and survival outcomes were evaluated. RESULTS: No bleeding complication was reported. One and two liver failures were respectively observed in sunitinib and placebo patients. Compliance to sunitinib treatment was acceptable. Sunitinib dose reduction occurred in 37% of patients due to acute toxicity. Main grade 3-4 toxicities were: thrombocytopenia, neutropenia, increased bilirubin, increased ALT and asthenia. In the sunitinib group, the median PFS and OS were 9.05 [5.81;11.63] and 25.0 [13.5;36.8] months, respectively. In the placebo group, the median PFS and OS were 5.51 [4.14;7.79] and 20.5 [15.1;30.6] months, respectively. CONCLUSIONS: TACE plus sunitinib in the first-line therapy for patients with HCC not suitable for surgical resection was feasible. CLINICALTRIALS. GOV NUMBER: NCT01164202.

Efficacy of per-oral endoscopic myotomy for the treatment of non-achalasia esophageal motor disorders.

INTRODUCTION: Per-oral endoscopic myotomy (POEM) is effective in achalasia. The objective of this study was to evaluate the short-term clinical efficacy of POEM in non-achalasia esophageal motility disorders (NAEMD). PATIENTS AND METHODS: Patients with NAEMD diagnosed by high-resolution manometry were included in a retrospective multicentric study. For each individual case, two controls paired on gender and age were matched: one with type I/II achalasia and one with type III achalasia. The clinical response, defined by an Eckardt score ≤ 3, was assessed at 3 and 6 months. RESULTS: Ninety patients (mean age 66 years, 57 men) were included, 30 patients with NAEMD (13 jackhammer esophagus, 6 spastic esophageal disorders, 4 nutcracker esophagus, and 7 esophagogastric junction obstruction), 30 patients with type I-II achalasia, and 30 patients with type III achalasia. The 3-month response rates were 80% (24/30), 90% (27/30), and 100% (30/30) in NAEMD, type I-II achalasia and type III achalasia, respectively (p < 0.01). Eckardt scores improved from preoperative baseline in all groups (median scores 2.0 after POEM vs. 6.5 before POEM, 1.3 vs. 7.2, and 0.5 vs. 6.1 in NAEMD, type I//I and Type III, respectively). No predictive factor of response was identified. In NAEMD patients, there was a significant improvement of dysphagia, regurgitation, and chest pain scores. The 6-month response rates were 63.2% (12/19), 95.5% (21/22), and 87.0% (20/23) in NAEMD, type I-II achalasia and type III achalasia, respectively (p = 0.03). CONCLUSION: Although less effective than in achalasia, POEM is an effective treatment for NAEMD. Long-term follow-up data are needed to further confirm that POEM may be a valid treatment of NAEMD.

Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus.

BACKGROUND: The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use. AIM: To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients. METHODS: A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors. RESULTS: Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naïve group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo. CONCLUSION: The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.

Impact of Obesity and Alanine Aminotransferase Levels on the Diagnostic Accuracy for Advanced Liver Fibrosis of Noninvasive Tools in Patients With Nonalcoholic Fatty Liver Disease.

INTRODUCTION: Some evidence suggests an interference of obesity and alanine aminotransferase (ALT) levels on the diagnostic accuracy for advanced fibrosis of noninvasive tools such as liver stiffness measurement (LSM) by FibroScan, Fibrosis-4 (FIB-4), and nonalcoholic fatty liver disease fibrosis score (NFS). We assessed whether the diagnostic accuracy of LSM, Fibrosis-4 (FIB-4), and NFS and strategies based on the combination of these tools is affected by obesity and/or ALT levels. METHODS: We analyzed data from 968 patients with a histological diagnosis of nonalcoholic fatty liver disease. FIB-4, NFS, and LSM by FibroScan were measured. RESULTS: LSM was better than both FIB-4 and NFS for staging F3-F4 fibrosis area under the receiver operating characteristic curve test (AUC) 0.863, 0.777, and 0.765, respectively; P < 0.001 for both), showing higher accuracy and higher negative predictive value (NPV), but lower positive predictive value (PPV). LSM worked less well in high ALT (>100 IU) (AUC 0.811 vs 0.877, P = 0.04; PPV 57.5% vs 62.4%; NPV 90.7% vs 94%) or obese patients (AUC 0.786 vs 0.902, P < 0.001; PPV 58.7% vs 64.8%; NPV 88.3% vs 95.2%), the latter not being affected by the M or XL probe. Consistently, LSM worked better in terms of AUC and accuracy compared with both FIB-4 and NFS only in nonobese or high ALT patients, even with always keeping a slightly lower PPV. A serial combination of FIB-4 or NFS with LSM as the second test in patients in the gray area of the first test retained-in most scenarios-similar PPV and NPV compared with LSM alone. These strategies also increased the diagnostic accuracy of about 20% in all groups of patients, even if with a lower overall accuracy in obese patients (71.3% and 67.1% for FIB-4 and NFS as the first test, respectively) compared to nonobese patients (81.9% and 82.4% for FIB-4 and NFS as the first test, respectively). CONCLUSIONS: All tested noninvasive tools have overall better NPV than PPV. LSM has a better diagnostic accuracy for advanced fibrosis than both FIB-4 and NFS only in nonobese and/or low ALT patients. Serial combination strategies are better than a single tool strategy, regardless of obesity and ALT levels, although the accuracy is lower in obese patients.

Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). Combining sorafenib with another treatment, to improve overall survival (OS) within an acceptable safety profile, might be the next step forward in the management of patients with advanced HCC. We aimed to assess whether a combination of sorafenib and a statin improved survival in patients with HCC. METHODS: The objective of the PRODIGE-11 trial was to compare the respective clinical outcomes of the sorafenib-pravastatin combination (arm A) versus sorafenib alone (arm B) in patients with advanced HCC. Child-Pugh A patients with advanced HCC who were naive to systemic treatment (n = 323) were randomly assigned to sorafenib-pravastatin combination (n = 162) or sorafenib alone (n = 161). The primary endpoint was OS; secondary endpoints were progression-free survival, time to tumor progression, time to treatment failure, safety, and quality of life. RESULTS: After randomization, 312 patients received at least 1 dose of study treatment. After a median follow-up of 35 months, 269 patients died (arm A: 135; arm B: 134) with no difference in median OS between treatments arms (10.7 months vs. 10.5 months; hazard ratio = 1.00; p = 0.975); no difference was observed in secondary survival endpoints either. In the univariate analysis, the significant prognostic factors for OS were CLIP score, performance status, and quality of life scores. The multivariate analysis showed that the only prognostic factor for OS was the CLIP score. The main toxicity was diarrhea (which was severe in 11% of patients in arm A, and 8.9% in arm B), while severe nausea-vomiting was rare, and no toxicity-related deaths were reported. CONCLUSION: Adding pravastatin to sorafenib did not improve survival in patients with advanced HCC. LAY SUMMARY: Sorafenib has proven efficacy for the treatment of patients with advanced hepatocellular carcinoma. However, overall survival remains poor in these patients, so we were interested to see if the addition of a statin, pravastatin, improved outcomes in patients with advanced HCC. This randomized-controlled trial demonstrated that the sorafenib-pravastatin combination did not improve overall survival in this study population compared to sorafenib alone. Clinical trial number: NCT01075555.

Assessment of Liver Disease Progression in Cystic Fibrosis Using Transient Elastography.

OBJECTIVES: Cystic fibrosis-related liver disease (CFLD) can develop silently in early life and approximately 10% of children with cystic fibrosis (CF) become cirrhotic before adulthood. Clinical, biological, and ultrasound criteria used to define CFLD often reveal liver involvement at an advanced stage. The aim of this retrospective study was to assess the progression of liver stiffness measurement (LSM) in pediatric patients with CF. METHODS: The change of LSM, expressed as kPa/year and %/year, was measured using transient elastography (Fibroscan) in 82 children with CF (median age: 6.8 years, interquartile range [IQR]: 5.8). Mean time interval between the 2 LSM was 3.5 years. RESULTS: Median initial liver stiffness was 3.7 kPa (IQR: 1.3), and then progressed by 0.23 kPa/year, that is, 6%/year. The 7 patients who developed CFLD had a higher initial level of alanine aminotransferase (50 [IQR: 15] vs 30 [IQR: 18], P = 0.0001) and presented a more rapid progression of LSM (0.94 vs 0.23 kPa/year, P = 0.02). CONCLUSIONS: The present study shows that the slope of worsening of liver stiffness is greater in patients who will develop CFLD, suggesting that annual transient elastography may be useful to detect risk of severe liver disease at an earlier stage.

Cirrhotic patients with portal hypertension-related bleeding and an indication for early-TIPS: a large multicentre audit with real-life results.

BACKGROUND: The Baveno VI consensus meeting concluded that an early TIPS must be considered in high-risk cirrhotic patients presenting with variceal bleeding (VB) (Child B + active bleeding at endoscopy or Child C10-13 patients). Whether this therapeutic approach is feasible in a real-life setting remains unclear. AIMS: To determine (1) the proportion of patients eligible for early-TIPS among cirrhotic patients with VB, (2) the proportion of these patients who underwent early-TIPS placement and the main reasons for discarding TIPS, and (3) the outcomes of patients who experienced early-TIPS placement in a large, national, prospective, multicentre audit including academic and non-academic centres. MATERIALS AND METHODS: All French centres recruiting gastrointestinal bleeding were invited to participate. All consecutive patients with cirrhosis and PHT-related bleeding were included. RESULTS: 964 patients were included (58 centres: 26 academic, 32 non-academic; patient characteristics: male sex, 77%; age, 59.6 ± 12.1 years; aetiologies of cirrhosis (alcoholic,viral/other, 67%/15%/18%); source of bleeding (EV/GV/other, 80/11/9%); active bleeding at endoscopy 34%; Child A 21%/B 44%/C 35%. Overall, 35% of the patients were eligible for early-TIPS, but only 6.8%, displaying less severe cirrhosis underwent early-TIPS placement. The main reason for discarding TIPS was a lack of availability. The actuarial probability of survival at one year was significantly increased in early-TIPS patients (85.7±0.07% vs 58.9±0.03%, p=0.04). The severity of liver disease was the only parameter independently associated with improved one-year survival. CONCLUSION: In this real-life study, one-third of the cirrhotic patients admitted for VB fulfilled the criteria for early-TIPS placement, whereas only 7% had access to TIPS. TIPS was restricted to patients displaying less severe cirrhosis. The severity of liver disease was the only parameter that influenced survival.

A Single Test Combining Blood Markers and Elastography is More Accurate Than Other Fibrosis Tests in the Main Causes of Chronic Liver Diseases.

BACKGROUND AND GOAL: International guidelines suggest combining a blood test and liver stiffness measurement (LSM) to stage liver fibrosis in chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD). Therefore, we compared the accuracies of these tests between the main etiologies of chronic liver diseases. STUDY: Overall, 1968 patients were included in 5 etiologies: CHC: 698, chronic hepatitis B: 152, human immunodeficiency virus/CHC: 628, NAFLD: 225, and alcoholic liver disease (ALD): 265. Sixteen tests [13 blood tests, LSM (Fibroscan), 2 combined: FibroMeters] were evaluated. References were Metavir staging and CHC etiology. Accuracy was evaluated mainly with the Obuchowski index (OI) and accessorily with area under the receiver operating characteristics (F≥2, F≥3, cirrhosis). RESULTS: OIs in CHC were: FibroMeters: 0.812, FibroMeters: 0.785 to 0.797, Fibrotest: 0.762, CirrhoMeters: 0.756 to 0.771, LSM: 0.754, Hepascore: 0.752, FibroMeter: 0.750, aspartate aminotransferase platelet ratio index: 0.742, Fib-4: 0.741. In other etiologies, most tests had nonsignificant changes in OIs. In NAFLD, CHC-specific tests were more accurate than NAFLD-specific tests. The combined FibroMeters had significantly higher accuracy than their 2 constitutive tests (FibroMeters and LSM) in at least 1 diagnostic target in all etiologies, except in ALD where LSM had the highest OI, and in 3 diagnostic targets (OIs and 2 area under the receiver operating characteristics) in CHC and NAFLD. CONCLUSIONS: Some tests developed in CHC outperformed other tests in their specific etiologies. Tests combining blood markers and LSM outperformed single tests, validating recent guidelines and extending them to main etiologies. Noninvasive fibrosis evaluation can thus be simplified in the main etiologies by using a unique test: either LSM alone, especially in ALD, or preferably combined to blood markers.

Controlled Attenuation Parameter (CAP) with the XL Probe of the Fibroscan®: A Comparative Study with the M Probe and Liver Biopsy.

INTRODUCTION: Controlled attenuation parameter (CAP) is a new method for the diagnosis of steatosis. Until now, CAP was available only with the M probe of the Fibroscan. The aim of this study was to evaluate the diagnostic performance of CAP with the XL probe versus CAP with the M probe, using liver biopsy (LB) as gold standard. PATIENTS AND METHODS: A total of 236 patients with chronic liver disease undergoing LB had CAP measurement with M and XL probes the same day. All LB were analyzed independently by two experienced pathologists. RESULTS: Median CAP was 240.5 and 239.5 dB/m with the M and XL probes, respectively. For the detection of steatosis grade with the M and XL probes, AUROCs were 0.82/0.83 for S ≥ 1, 0.89/0.88 for S ≥ 2, and 0.92/0.93 for S3, respectively. Cutoffs were (M and XL probes) 246/242 for S ≥ 1, 269/267 for S ≥ 2, and 285/286 dB/m for S3, respectively. The factor significantly associated with CAP with the M and XL probes was steatosis grade. In multivariate analysis, a low CAP value with XL probe was negatively associated with waist circumference, triglycerides, albumin, and the alcohol consumption, and positively with alkaline phosphatases. In multivariate analysis, a high CAP value with the XL probe was positively associated with waist circumference and triglycerides. CONCLUSION: CAP with the XL probe is a new tool for the diagnosis of steatosis. This parameter could be useful for the diagnosis and the follow-up of obese patients.

Validity criteria for the diagnosis of fatty liver by M probe-based controlled attenuation parameter.

BACKGROUND & AIMS: Controlled attenuation parameter (CAP) can be performed together with liver stiffness measurement (LSM) by transient elastography (TE) and is often used to diagnose fatty liver. We aimed to define the validity criteria of CAP. METHODS: CAP was measured by the M probe prior to liver biopsy in 754 consecutive patients with different liver diseases at three centers in Europe and Hong Kong (derivation cohort, n=340; validation cohort, n=414; 101 chronic hepatitis B, 154 chronic hepatitis C, 349 non-alcoholic fatty liver disease, 37 autoimmune hepatitis, 49 cholestatic liver disease, 64 others; 277 F3-4; age 52±14; body mass index 27.2±5.3kg/m2). The primary outcome was the diagnosis of fatty liver, defined as steatosis involving ≥5% of hepatocytes. RESULTS: The area under the receiver-operating characteristics curve (AUROC) for CAP diagnosis of fatty liver was 0.85 (95% CI 0.82-0.88). The interquartile range (IQR) of CAP had a negative correlation with CAP (r=-0.32, p<0.001), suggesting the IQR-to-median ratio of CAP would be an inappropriate validity parameter. In the derivation cohort, the IQR of CAP was associated with the accuracy of CAP (AUROC 0.86, 0.89 and 0.76 in patients with IQR of CAP <20 [15% of patients], 20-39 [51%], and ≥40dB/m [33%], respectively). Likewise, the AUROC of CAP in the validation cohort was 0.90 and 0.77 in patients with IQR of CAP <40 and ≥40dB/m, respectively (p=0.004). The accuracy of CAP in detecting grade 2 and 3 steatosis was lower among patients with body mass index ≥30kg/m2 and F3-4 fibrosis. CONCLUSIONS: The validity of CAP for the diagnosis of fatty liver is lower if the IQR of CAP is ≥40dB/m. Lay summary: Controlled attenuation parameter (CAP) is measured by transient elastography (TE) for the detection of fatty liver. In this large study, using liver biopsy as a reference, we show that the variability of CAP measurements based on its interquartile range can reflect the accuracy of fatty liver diagnosis. In contrast, other clinical factors such as adiposity and liver enzyme levels do not affect the performance of CAP.

EASL and AASLD recommendations for the diagnosis of HCC to the test of daily practice.

AIMS: To evaluate the diagnostic performance of CT, MRI and CEUS alone and in combination, for the diagnosis of HCC between 10 and 30 mm, in a large population of cirrhotic patients. PATIENTS AND METHODS: In a multicentre prospective trial, 442 patients have been enrolled. Within a month, CEUS, CT and MRI were performed for all patients. A composite algorithm was defined to obtain the more accurate gold standard. RESULTS: A total of 544 nodules in 381 patients have been retained for the performance analysis. Eighty-two percent of the patients were male, mean age was 62 years. For the 10-20 mm nodules (n=342), the sensitivity (Se) and specificity (Sp) for the diagnosis of HCC were, respectively, 70.6% and 83.2% for MRI, 67.9% and 76.8% for CT and 39.6% and 92.9% for CEUS. For the 20-30 mm nodules (n=202), the Se and Sp were, respectively, 72.3% and 89.4% for MRI, 71.6% and 93.6% for CT and 52.9% and 91.5% for CEUS. THE BEST COMBINATION FOR THE 10-20 MM NODULES WAS MRI + CT (SE: 55.1%, SP: 100.0%).: After a first inconclusive technique, CEUS as second image technique allowed the highest specificity with only a slight drop of sensitivity for 10-20 mm nodules and the highest sensitivity and specificity for 20-30 mm nodules. CONCLUSION: This large multicentre study validates the EASL/AASLD recommendations in daily practice. Specificity using CT or MRI in 10-20 mm HCC was low, but we do not recommend combined imaging at first as sensitivity would be very low. The best sequential approach combined MRI and CEUS.

Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values.

Liver stiffness measurement (LSM) frequently overestimates the severity of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). Controlled attenuation parameter (CAP) is a new parameter provided by the same machine used for LSM and associated with both steatosis and body mass index, the two factors mostly affecting LSM performance in NAFLD. We aimed to determine whether prediction of liver fibrosis by LSM in NAFLD patients is affected by CAP values. Patients (n = 324) were assessed by clinical and histological (Kleiner score) features. LSM and CAP were performed using the M probe. CAP values were grouped by tertiles (lower 132-298, middle 299-338, higher 339-400 dB/m). Among patients with F0-F2 fibrosis, mean LSM values, expressed in kilopascals, increased according to CAP tertiles (6.8 versus 8.6 versus 9.4, P = 0.001), and along this line the area under the curve of LSM for the diagnosis of F3-F4 fibrosis was progressively reduced from lower to middle and further to higher CAP tertiles (0.915, 0.848-0.982; 0.830, 0.753-0.908; 0.806, 0.723-0.890). As a consequence, in subjects with F0-F2 fibrosis, the rates of false-positive LSM results for F3-F4 fibrosis increased according to CAP tertiles (7.2% in lower versus 16.6% in middle versus 18.1% in higher). Consistent with this, a decisional flowchart for predicting fibrosis was suggested by combining both LSM and CAP values. CONCLUSIONS: In patients with NAFLD, CAP values should always be taken into account in order to avoid overestimations of liver fibrosis assessed by transient elastography. (Hepatology 2017;65:1145-1155).

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.

Risk of Incident Cancer in Inflammatory Bowel Disease Patients Starting Anti-TNF Therapy While Having Recent Malignancy.

BACKGROUND: Patients with inflammatory bowel disease (IBD) and history of malignancy within the last 5 years are usually contraindicated for receiving anti-tumor necrosis factor (anti-TNF) agents. The aim of this study is to assess survival without incident cancer in a cohort of IBD patients exposed to anti-TNF while having previous malignancy within past 5 years. METHODS: Data from IBD patients with previous malignancy diagnosed within the last 5 years before starting an anti-TNF agent were collected through a Groupe d'Etude Thérapeutiques des Affections Inflammatoires du tube Digestif multicenter survey. Inclusion date corresponded to the first anti-TNF administration after cancer diagnosis. RESULTS: Twenty centers identified 79 cases of IBD patients with previous malignancy diagnosed 17 months (median; range: 1-65) before inclusion. The most frequent cancer locations were breast (n = 17) and skin (n = 15). After a median follow-up of 21 (range: 1-119) months, 15 (19%) patients developed incident cancer (8 recurrent and 7 new cancers), including 5 basal-cell carcinomas. Survival without incident cancer was 96%, 86%, and 66% at 1, 2, and 5 years, respectively. Crude incidence rate of cancer was 84.5 (95% CI, 83.1-85.8) per 1000 patient-years. CONCLUSIONS: In a population of refractory IBD patients with recent malignancy, anti-TNF could be used taking into account a mild risk of incident cancer. Pending prospective and larger studies, a case-by-case joint decision taken with the oncologist is recommended for managing these patients in daily practice.

Early diagnosis of NAFLD-NASH transition using mid infrared spectroscopy.

Non-alcoholic fatty liver disease (NAFLD) is defined as an excessive accumulation of fat in the liver in the absence of excessive drinking of alcohol. Initially considered as benign and self-limited, NAFLD may progress to the malignant stage of non-alcoholic steatohepatitis (NASH) characterized by degenerate hepatocellular ballooning and lobular inflammation. NASH can lead to hepatic fibrosis and ultimately to cirrhosis and hepatocellular carcinoma. Unfortunately, the transition from NAFLD to NASH is difficult to detect so far. In this paper, we propose to evaluate the characterization of NASH using mid infrared fiber evanescent wave spectroscopy on blood serum. We used an heuristic variable selection method and a generalized linear model to classify NAFLD and NASH spectra. The obtained results proved that this technique is a promising non-invasive and simple diagnosis tool for NASH.

Controlled attenuation parameter for the diagnosis of steatosis in non-alcoholic fatty liver disease.

BACKGROUND AND AIM: Controlled attenuation parameter (CAP) evaluated with transient elastography (FibroScan) is a recent method for non-invasive assessment of steatosis. Its usefulness in non-alcoholic fatty liver disease (NAFLD) is unknown. We prospectively investigated the performance of CAP for the diagnosis of steatosis in NAFLD, factors associated with discordances between CAP and steatosis grades, and relationships between CAP and clinical or biological parameters. METHODS: All CAP examinations performed in NAFLD patients with a liver biopsy performed within 1 week of CAP measurement were included. Liver biopsies were assessed for activity and fibrosis stage, NAFLD activity score, and steatosis graded as follows: S0, steatosis < 5%; S1, 5-33%; S2, 34-66%; S3, >66%. RESULTS: Two hundred sixty-one patients (59% male, age 56 years) from two ethnic groups were included. No patient had steatosis < 5%. The area under the receiver-operating characteristics curve of CAP for steatosis ≥S2 and S3 was 0.80 and 0.66, respectively. At a cut-off value of 310 dB/m, the sensitivity, specificity, and positive and negative predictive values for ≥S2 steatosis were 79%, 71%, 86%, and 71%, respectively. Discordance of at least one grade between CAP and steatosis was observed in 81 patients. By multivariate analysis, only steatosis S2S3 was associated with no discordance. By multivariate analysis, only BMI ≥ 30 kg/m(2) was significantly associated with CAP > 310 dB/m. CONCLUSION: The association of CAP with steatosis, especially in patients with non-alcoholic steatohepatitis, and with elevated BMI could be useful for the diagnosis and follow-up of NAFLD patients.

Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) has become a major public health issue. The goal of this study was to assess the clinical use of liver stiffness measurement (LSM) evaluated by supersonic shear imaging (SSI), FibroScan, and acoustic radiation force impulse (ARFI) in a cohort of NAFLD patients who underwent liver biopsy. A total of 291 NAFLD patients were prospectively enrolled from November 2011 to February 2015 at 2 French university hospitals. LSM was assessed by SSI, FibroScan (M probe), and ARFI within two weeks prior to liver biopsy. Calculations of the area under the receiver operating curve (AUROC) were performed and compared for the staging of liver fibrosis. AUROC for SSI, FibroScan, and ARFI were 0.86, 0.82, and 0.77 for diagnoses of ≥F2; 0.89, 0.86, and 0.84 for ≥F3; and 0.88, 0.87, and 0.84 for F4, respectively. SSI had a higher accuracy than ARFI for diagnoses of significant fibrosis (≥F2) (P = 0.004). Clinical factors related to obesity such as body mass index ≥ 30 kg/m(2) , waist circumference ≥102 cm or increased parietal wall thickness were associated with LSM failures when using SSI or FibroScan and with unreliable results when using ARFI. In univariate analysis, FibroScan values were slightly correlated with NAFLD activity score and steatosis (R = 0.28 and 0.22, respectively), whereas SSI and ARFI were not; however, these components of NAFLD did not affect LSM results in multivariate analysis. The cutoff values for SSI and FibroScan for staging fibrosis with a sensitivity ≥90% were very close: 6.3/6.2 kPa for ≥F2, 8.3/8.2 kPa for ≥F3, and 10.5/9.5 kPa for F4. CONCLUSION: Although obesity is associated with an increase in LSM failure, the studied techniques and especially SSI provide high value for the diagnosis of liver fibrosis in NAFLD patients. (Hepatology 2016;63:1817-1827).

Liver stiffness measurements for evaluation of central venous pressure in congenital heart diseases.

OBJECTIVE: Transient elastography (TE; Fibroscan, Echosens, France) is a non-invasive and reproducible approach to assess liver stiffness (LS). LS has been reported to be associated with fibrosis but central venous pressure (CVP) can also influence LS values. We sought to evaluate the correlation between LS and CVP in a large cohort of children and adults with congenital heart disease. METHODS: All patients referred in our institution between 2012 and 2013 for diagnostic or interventional right heart catheterisation (RHC) were prospectively enrolled excluding patients with acute heart failure, chronic alcohol abuse, chronic liver disease, severe obesity and ascites. Patients underwent LS measurement and CVP measurement by RHC under general anaesthesia within the same or subsequent day. RESULTS: Sixty children (7.4±5.5 years) and 36 adults (38±16 years) were included. Median CVP was 6 mm Hg (range 3-15), median LS was 5 kPa (range 2.8-47.2). LS significantly correlated with CVP (r=0.75, p<10(-4)). In the two subgroups (ie, children and adults), correlation was r=0.68 and r=0.84 (p<10(-4)), respectively. In the overall population, the area under the curve of LS for identification of CVP >10 mm Hg was 0.972 (95% CI 0.855 to 1; p<0.05). Optimal cut-off value of LS for detection of CVP >10 mm Hg was 8.8 kPa (sensitivity=91.67%, specificity=96.25%). CONCLUSIONS: LS measurement using TE is a rapid and reliable method to evaluate CVP in patients with congenital heart disease.

MR relaxometry in chronic liver diseases: Comparison of T1 mapping, T2 mapping, and diffusion-weighted imaging for assessing cirrhosis diagnosis and severity.

BACKGROUND: MR relaxometry has been extensively studied in the field of cardiac diseases, but its contribution to liver imaging is unclear. We aimed to compare liver and spleen T1 mapping, T2 mapping, and diffusion-weighted MR imaging (DWI) for assessing the diagnosis and severity of cirrhosis. METHODS: We prospectively included 129 patients with normal (n=40) and cirrhotic livers (n=89) from May to September 2014. Non-enhanced liver T1 mapping, splenic T2 mapping, and liver and splenic DWI were measured and compared for assessing cirrhosis severity using Child-Pugh score, MELD score, and presence or not of large esophageal varices (EVs) and liver stiffness measurements using Fibroscan(®) as reference. RESULTS: Liver T1 mapping was the only variable demonstrating significant differences between normal patients (500±79ms), Child-Pugh A patients (574±84ms) and Child-Pugh B/C patients (690±147ms; all p-values <0.00001). Liver T1 mapping had a significant correlation with Child-Pugh score (Pearson's correlation coefficient of 0.46), MEDL score (0.30), and liver stiffness measurement (0.52). Areas under the receiver operating characteristic curves of liver T1 mapping for the diagnosis of cirrhosis (O.85; 95% confidence intervals (CI), 0.77-0.91), Child-Pugh B/C cirrhosis (0.87; 95%CI, 0.76-0.93), and large EVs (0.75; 95%CI, 0.63-0.83) were greater than that of spleen T2 mapping, liver and spleen DWI (all p-values<0.01). CONCLUSION: Liver T1 mapping is a promising new diagnostic tool for assessing cirrhosis diagnosis and severity, showing higher diagnostic accuracy than liver and spleen DWI, while T2 mapping is not reliable.

Liver and spleen elastography using supersonic shear imaging for the non-invasive diagnosis of cirrhosis severity and oesophageal varices.

BACKGROUND: Elastography is a promising non-invasive approach for assessing liver fibrosis. We assessed diagnostic performances of liver and spleen stiffness using supersonic shear imaging for diagnosing cirrhosis severity and oesophageal varices. METHODS: 401 consecutive cirrhotic patients were prospectively enrolled from November 2012 to March 2014. All patients underwent liver and spleen stiffness measurement with supersonic shear imaging and Fibroscan. RESULTS: Failures of measurement were 6.2% and 29.2% for liver and spleen stiffness (supersonic shear imaging), and 18.4% for liver stiffness (Fibroscan). Liver and spleen stiffness were correlated with severity of cirrhosis, with values increasing according to Child-Pugh subclasses and presence of complications. With a negative predictive value ≥90%, liver stiffness cut-offs for high-risk oesophageal varices, history of ascites, Child-Pugh B/C, variceal bleeding and clinical decompensation were 12.8, 19, 21.4, 30.5, and 39.4 kPa, respectively. Areas under the curve of spleen and liver stiffness (supersonic shear imaging), and liver stiffness (Fibroscan) were 0.80, 0.77 and 0.73 respectively for detection of oesophageal varices. CONCLUSION: Liver stiffness using supersonic shear imaging is a relevant diagnostic tool for assessing cirrhosis severity and its complications. Spleen stiffness shows promising results for the detection of oesophageal varices but is not yet sufficiently robust for clinical practice owing to high failure rates.