Pathophysiological changes of the liver-muscle axis in end-stage liver disease: what is the right target?

Liver diseases and in particular end stage liver diseases are frequently complicated by muscle modifications that are linked to worse clinical outcome. In addition, recent studies have demonstrated the negative impact of these muscle changes on liver function leading to the hypothesis of a bidirectional relationship referred in the literature as "muscle-liver axis". In a context of evolution towards a more holistic and less organocentric vision of medicine, studying frailty, myosteatosis and sarcopenia and their underlying pathophysiological mechanisms has led to many publications in the last five years. These studies are describing several pathophysiological mechanisms, highlighting the extremely complex character of this relationship. This review aims to summarize these mechanisms as well as potential therapeutic targets, independently of liver disease etiology

combined hepatocellular-cholangiocarcinoma : epidemiological, radiological and survival data from a monocenter retrospective study

Introduction : Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver malignancy with a poor prognosis and very few available data in terms of pathophysiology, risk factors, imaging features and no current consensus in terms of treatment recommendations. Therefore, our aims were to assess the risk factors, imaging-pathology correlation and survival of cHCC-CCA compared to other malignant liver tumours (hepatocarcinoma (HCC) and cholangiocarcinoma (CCA)). Methods : All patients with histologically-confrmed or with imaging-based suspicion of cHCC-CCA (classifed Li-Rads M) treated between 2016 and 2021 in the Cliniques Saint-Luc were screened in a retrospective single-center study. Other histological subtypes of liver tumor in the absence of radiological suspicion of mixed tumor by magnetic resonance imaging (MRI) were excluded. Patients with other histological subtypes or non histologically assessed were included in the non-HCC-CCA group. MRI data of transplanted patients were not recorded considering the artifacts due to waiting treatments. Treatment modalities were defned as HCC regimen if included anti-VEGF drugs or as CCA regimen if included a chemotherapy combining Gemcitabine and a platinum salt. All data were recorded based on medical records. Results : Among 761 screened patients, 57 patients (7.5%) were included among which 26 patients with histologically confrmed cHCCCCA (cHCC-CCA group - 45.6%), 18 patients with HCC ( HCC group - 31.6%), 9 patients with CCA (CCA group - 15.8%) and 4 patients with benign tumor (7%). 735 patients (92.5%) were included in the non-HCC-CCA group. In terms of imaging diagnostic accury in the HCC-CCA group (N=26), 17 patients had a positive MRI for HCC-CCA (65.4%) and 9 had a negative MRI (34.6%). In the non-HCC-CCA group (N = 735), 31 patients had a positive MRI (4.2 %) and 704 had a negative MRI (95.8 %) (Sensitivity = 0.65; Specifcity = 0.96; positive predictive value = 0.35 (PPV); negative predictive value = 0.99 (NPV); p<0.0001). In terms of median survival, no signifcant differences were observed between histological subgroups (cHCC-CCA : 44.77 months; CCA : undefned; HCC : 37.61 – p=0.81). No signifcant differences were also observed in the cHCC-CCA group depending on treatment modality (liver directed therapy : 44.8 months; systemic treatment : 26.86 – p=0.14). Take home messages : ● Liver MRI has an excellent NPV for the diagnosis of cHCCCCA. ● Median survival does not differ according to histological subtype. ● Median survival does not differ in the cHCC-CCA group according to treatment modalit

Modelling to Simulate Botnet Command and Control Protocols for the Evaluation of Network Intrusion Detection Systems

National audienceThe purpose of this paper is the modelization and simulation of zombie machines for the evaluation of Network Intrusion Detection Systems (NIDS), used to detect botnets. We propose an automatic method to infer zombies behaviors through the analysis of messages exchanged with their masters. Once computed, a model provides a solution to generate realistic and manageable traffic, which is mandatory for an NIDS evaluation. We propose to use a Stochastic Mealy Machine to model zombies behavior, and an active inference algorithm to learn it. With our approach, it is possible to generate a realistic traffic corresponding to the communications of botnets while ensuring its controllability in the context of an NIDS evaluation

Myosteatosis: diagnosis, pathophysiology and consequences in metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) sets an increased risk of multisystemic complications, including muscle changes with sarcopenia and more recently myosteatosis that could reciprocally affect liver function. We conducted a systematic review to highlight innovative assessment tools, pathophysiological mechanisms and metabolic consequences related to myosteatosis in MASLD, based on original articles screened from PUBMED, EMBASE and COCHRANE databases. Forty-six original manuscripts (14 preclinical and 32 clinical studies) were included. Microscopy (8/14) and tissue lipid extraction (8/14) are the two main assessment techniques used for muscle lipid content in pre-clinical studies. In clinical studies, imaging is the most used assessment tool and included computed tomography (14/32), magnetic resonance imaging (12/32) and ultrasound (4/32). Assessed muscles varied across studies but mainly included paravertebral (4/14 in pre-clinical; 13/32 in clinical studies) and lower limbs muscles (10/14 in preclinical; 13/32 in clinical studies). Myosteatosis is highly prevalent already in non-cirrhotic stages of MASLD and correlates with disease activity when using muscle density assessed by computed tomography. Numerous pathophysiological mechanisms were found and included: high-fat and high-fructose diet, dysregulation in fatty acids transport and ketogenesis, endocrine disorders and impaired microRNA122 pathway. This review also evidenced several potential consequences related to myosteatosis in MASLD such as insulin resistance, MASLD progression from steatosis to metabolic steatohepatitis and loss of muscle strength. In conclusion, several data on myosteatosis in MASLD are already available. Myosteatosis could appear as a muscle change highly relevant to screen considering its correlation with MASLD activity as well as its related consequences. Recent innovative imaging techniques allow to accurately assess myosteatosis

Frailty in metabolic dysfunction-associated fatty liver disease is related to the presence of diabetes and the severity of liver fibrosis

Background and Aims: Frailty is very common in end-stage liver disease, regardless of disease etiology, and has a significant impact on clinical outcome and quality of life, due to impaired skeletal muscle function, quality and quantity. However, there are few data available on the relationship between liver and skeletal muscle, especially in patients with earlier disease stages. Our aims are to evaluate the prevalence of frailty in a prospective cohort of patients with metabolic-dysfunction associated fatty liver disease (MAFLD) according to its severity. Method: Patients with MAFLD were recruited in a prospective single-center cohort study. Epidemiological, clinical, biological and anthropometric data were collected. All patients underwent a noninvasive assessment for frailty screening, including a dominant hand grip strength test, a balance test, and the time required to do five times sit to stand to calculate the liver frailty index (LFI). The severity of MAFLD was assessed by the fatty liver index (FLI), fibrosis 4 (FIB-4) index, and by transient elastography (elasticity and controlled attenuation parameter). Results: 92 patients with MAFLD were recruited, including 44 men (47.8 %) and 44 patients with type 2 diabetes (47.8 %). Mean age was 55 years (19-78), mean BMI was 32.7 kg/m² (23.9 - 47.5) and mean HOMA-IR was 7.6 (0.5-30.1). Regarding the severity of MAFLD, the mean elasticity was 6.45 KPa (3.1 - 35) and the mean FIB-4 score was 1.33 (0.31 - 5.61). The mean FLI was 85.1 (28-100) and the mean controlled attenuation parameter (CAP) was 332.3 dB/m (207-400). Regarding frailty parameters, the mean dominant grip strength was 31 kg (8 - 62), the mean time to do five chair stands was 8.2 seconds (4.25 - 24.25), the mean balance test score was 9.9 seconds (2.1 - 10) and the mean LFI was 2.98 (1.13 - 4.71). 51 patients had an LFI score 2.67 vs 2.8 in case of FIB-4 < 1.3 (p = 0.042) (Figure). Conclusion: 44% of MAFLD patients already have a frail or pre-frail status regardless of age. This reduction of strength is associated with the presence of diabetes and the severity of MAFLD in terms of fibrosis. Further research is needed to determine the cause of this frailty and its potential impact on liver disease severity and prognosis

Unlocking liver health: Can tackling myosteatosis spark remission in metabolic dysfunction-associated steatotic liver disease?

Myosteatosis is highly prevalent in metabolic dysfunction-associated steatotic liver disease (MASLD) and could reciprocally impact liver function. Decreasing muscle fat could be indirectly hepatoprotective in MASLD. We conducted a review to identify interventions reducing myosteatosis and their impact on liver function. Non-pharmacological interventions included diet (caloric restriction or lipid enrichment), bariatric surgery and physical activity. Caloric restriction in humans achieving a mean weight loss of 3% only reduces muscle fat. Lipid-enriched diet increases liver fat in human with no impact on muscle fat, except sphingomyelin-enriched diet which reduces both lipid contents exclusively in pre-clinical studies. Bariatric surgery, hybrid training (resistance exercise and electric stimulation) or whole-body vibration in human decrease both liver and muscle fat. Physical activity impacts both phenotypes by reducing local and systemic inflammation, enhancing insulin sensitivity and modulating the expression of key mediators of the muscle-liver-adipose tissue axis. The combination of diet and physical activity acts synergistically in liver, muscle and white adipose tissue, and further decrease muscle and liver fat. Several pharmacological interventions (patchouli alcohol, KBP-089, 2,4-dinitrophenol methyl ether, adipoRon and atglistatin) and food supplementation (vitamin D or resveratrol) improve liver and muscle phenotypes in pre-clinical studies by increasing fatty acid oxidation and anti-inflammatory properties. These interventions are effective in reducing myosteatosis in MASLD while addressing the liver disease itself. This review supports that disturbances in inter-organ crosstalk are key pathophysiological mechanisms involved in MASLD and myosteatosis pathogenesis. Focusing on the skeletal muscle might offer new therapeutic strategies to treat MASLD by modulating the interactions between liver and muscles

Impact of peroxisome proliferator-activated receptor agonists on myosteatosis in the context of metabolic dysfunction-associated steatotic liver disease

Introduction : A growing body of evidence suggests that metabolic dysfunction-associated steatotic liver disease (MASLD) could be associated with fatty infiltration of skeletal muscles, known as myosteatosis. Myosteatosis is implicated in the development of insulin resistance by altering the insulin signalling pathway, could affect muscle function and possibly contributes to the severity of liver damage. A combination of peroxisome proliferator-activated receptor (PPAR) agonists is currently being evaluated as a promising treatment for metabolic dysfunction-associated steatohepatitis (MASH), the inflammatory stage of MASLD. However, the effect of pan-PPAR agonists on myosteatosis remains to be determined. Objective: The aim of this systematic review is to evaluate the effect of PPAR agonists and their combination on myosteatosis in the context of MASLD. Methods: We searched for combination of terms including NAFLD, MAFLD, NASH, PPAR agonist, muscle fat and intramyocellular lipids published until March 2023 using PubMed and EMBASE. Only original articles have been retained. Articles were carefully selected and examined in order to identify relevant results that align with our research topic. Results: Our search yielded 34 results. After reading the titles and removing duplicates, 24 articles were evaluated according to our inclusion criteria. Eleven original manuscript articles were retained to answer our research question. The impact of the PPARα agonist on myosteatosis was assessed by triglyceride extraction in two preclinical studies in rats on a high-fat diet (HFD) and in insulin-resistant mice, and by proton magnetic resonance spectroscopy (MRS) in a clinical study in healthy and insulin-resistant elderly subjects. In rats fed a HFD, a two-week treatment significantly reduced quadriceps muscle triglyceride levels (-34%), as well as liver triglyceride levels (-54%), compared with controls. In insulin-resistant rats, it reduced quadriceps muscle (-44%) and liver (-40%) triglyceride levels compared to untreated rats. In a clinical study, a 60-day course of the PPARα agonist fenofibrate had no significant impact on soleus intramyocellular lipids (IMCL) or liver fat content in either insulin-resistant subjects or the healthy elderly group. In two studies on myocytes, treatment with PPARδ agonist increased the expression of the fatty acid oxidation genes CD36 and CPT1b. PPARγ agonists have been the subject of two preclinical studies and one clinical study. In the first preclinical study in Zucker diabetic fatty (ZDF) rats, treatment for one week with the PPARγ agonist rosiglitazone reduced IMCL (-40%) and hepatic steatosis (-89%) assessed by MRS and compared with the control group of ZDF rats, but had no impact on extramyocellular lipids. In a second preclinical study on ZDF rats, the PPARγ agonist pioglitazone reduced anterior tibial IMCL (-43%) assessed by proton MRS. In contrast, one year's treatment with rosiglitazone significantly increased the surface area of low density muscles (suggesting muscle fat infiltration) assessed by CT scan in patients with type 2 diabetes, while no change was observed in the placebo group. Combinations of PPAR agonists were evaluated in two preclinical studies and one clinical study. In the first preclinical study in ZDF rats on a HFD, cevoglitazar (a dual PPARα/γ agonist) significantly reduced the IMCL of the tibialis anterior, comparable to treatment with the PPARα agonist fenofibrate and the PPARγ agonist pioglitazone alone. Only fenofibrate and cevoglitazar significantly reduced hepatocellular lipids (MRS). In another preclinical study in ZDF rats, the combination of fenofibrate (PPARα) and rosiglitazone (PPARγ) did not significantly reduce gastrocnemius muscle triglyceride content (assessed by triglyceride extraction), but did with fenofibrate alone. In addition, gastrocnemius intramuscular triglyceride content was increased in ZDF rats treated with rosiglitazone alone. In contrast, in the latest clinical trial in type 2 diabetic patients, a 4-month treatment with the PPARα/γ agonist muraglitazar significantly decreased IMCL of the tibialis anterior as well as liver fat content assessed by MRS. Conclusion: PPAR agonists, and more specifically their combination, are a promising treatment for MASH and could also have a positive impact on reducing myosteatosis. The few discrepancies noted between the studies could be explained by the different techniques used to assess myosteatosis and the possible adipogenic effect of PPARγ agonists. Further clinical research is required to fully evaluate the efficacy of these treatments on both MASH components and myosteatosis. We believe that myosteatosis should be adequately evaluated in future studies on MASLD/MASH

Development of a drug-disease simulation model for rituximab in follicular non-Hodgkin's lymphoma

International audiencecenter dot Serum concentrations of rituximab influence its clinical efficacy in follicular lymphoma (FL), but its concentration-effect relationship has not been described by pharmacokinetic-pharmacodynamic (PK-PD) modelling. center dot The genetic polymorphism of FCGR3A influences rituximab efficacy and its in vitro concentration-effect relationship. center dot Increasing rituximab dose and/or number of infusions may lead to a better clinical response in FL. WHAT THIS PAPER ADDS center dot This study is the first to describe the concentration-effect relationship of rituximab in populations of FL patients. center dot This PK-PD model relates progression-free survival with rituximab concentrations and takes into account the influence of FCGR3A polymorphism. center dot Clinical trials testing new dosing regimens of rituximab can be designed using this PK-PD model. AIM Rituximab has dramatically improved the survival of patients with non-Hodgkin's lymphomas (NHL), but the dosing regimen currently used should be optimized. However, the concentration-effect relationship of rituximab has never been described by pharmacokinetic-pharmacodynamic (PK-PD) modelling, precluding the simulation of new dosing regimens. The aim of this study was to develop a PK-PD model of rituximab in relapsed/resistant follicular NHL (FL). METHODS A model describing the relationship between rituximab concentrations and progression-free survival (PFS) was developed using data extracted from the pivotal study, which evaluated 151 relapsed/resistant FL patients. The influence of FCGR3A genetic polymorphism on the efficacy of rituximab was quantified using data from 87 relapsed/resistant FL patients. The predictive performance of the model was analysed using two independent datasets: a study that evaluated rituximab combined with chemotherapy [rituximab, cyclophosphamide, vincristine, adriamycin and prednisone (R-CHOP)] in 334 relapsed/resistant FL patients and a study that evaluated rituximab monotherapy in 47 asymptomatic FL patients with known FCGR3A genotype. RESULTS For R-CHOP, observed and model-predicted PFS (90% confidence interval) at 24 months were 0.50 and 0.48 (0.40, 0.56), respectively, for the observation arm, and 0.62 and 0.59 (0.50, 0.65), respectively, for the rituximab maintenance arm. For rituximab monotherapy, observed and predicted PFS at 24 months were 0.67 and 0.63, respectively, for FCGR3A-V/V patients, and 0.41 and 0.36 (0.25, 0.49), respectively, for FCGR3A-F carriers. CONCLUSIONS Our model provides a satisfactory prediction of PFS at 24 months. It can be used to simulate new dosing regimens of rituximab in populations of FL patients and should improve the design of future clinical trials

Model-based design of rituximab dosing optimization in follicular non-hodgkin lymphoma

International audienc