The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche.

Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro-fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro-inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated ΔEGFR mice when compared with CCl4-treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-fibrotic and pro-inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase-dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Intrinsic cancer cell phosphoinositide 3-kinase δ regulates fibrosis and vascular development in cholangiocarcinoma.

BACKGROUND & AIMS: The class I- phosphatidylinositol-3 kinases (PI3Ks) signalling is dysregulated in almost all human cancers whereas the isoform-specific roles remain poorly investigated. We reported that the isoform δ (PI3Kδ) regulated epithelial cell polarity and plasticity and recent developments have heightened its role in hepatocellular carcinoma (HCC) and solid tumour progression. However, its role in cholangiocarcinoma (CCA) still lacks investigation. APPROACH & RESULTS: Immunohistochemical analyses of CCA samples reveal a high expression of PI3Kδ in the less differentiated CCA. The RT-qPCR and immunoblot analyses performed on CCA cells stably overexpressing PI3Kδ using lentiviral construction reveal an increase of mesenchymal and stem cell markers and the pluripotency transcription factors. CCA cells stably overexpressing PI3Kδ cultured in 3D culture display a thick layer of ECM at the basement membrane and a wide single lumen compared to control cells. Similar data are observed in vivo, in xenografted tumours established with PI3Kδ-overexpressing CCA cells in immunodeficient mice. The expression of mesenchymal and stemness genes also increases and tumour tissue displays necrosis and fibrosis, along with a prominent angiogenesis and lymphangiogenesis, as in mice liver of AAV8-based-PI3Kδ overexpression. These PI3Kδ-mediated cell morphogenesis and stroma remodelling were dependent on TGFß/Src/Notch signalling. Whole transcriptome analysis of PI3Kδ using the cancer cell line encyclopedia allows the classification of CCA cells according to cancer progression. CONCLUSIONS: Overall, our results support the critical role of PI3Kδ in the progression and aggressiveness of CCA via TGFß/src/Notch-dependent mechanisms and open new directions for the classification and treatment of CCA patients.

Role of EpCAM+ CD133+ extracellular vesicles in steatosis to steatohepatitis transition in NAFLD.

BACKGROUND AND AIMS: Extracellular vesicles (EVs) have emerged as a potential source of circulating biomarkers in liver disease. We evaluated circulating AV+ EpCAM+ CD133+ EVs as a potential biomarker of the transition from simple steatosis to steatohepatitis. METHODS: EpCAM and CD133 liver proteins and EpCAM+ CD133+ EVs levels were analysed in 31 C57BL/6J mice fed with a chow or high fat, high cholesterol and carbohydrates diet (HFHCC) for 52 weeks. The hepatic origin of MVs was addressed using AlbCrexmT/mG mice fed a Western (WD) or Dual diet for 23 weeks. Besides, we assessed plasma MVs in 130 biopsy-proven NAFLD patients. RESULTS: Hepatic expression of EpCAM and CD133 and EpCAM+ CD133+ EVs increased during disease progression in HFHCC mice. GFP+ MVs were higher in AlbCrexmT/mG mice fed a WD (5.2% vs 12.1%) or a Dual diet (0.5% vs 7.3%). Most GFP+ MVs were also positive for EpCAM and CD133 (98.3% and 92.9% respectively), suggesting their hepatic origin. In 71 biopsy-proven NAFLD patients, EpCAM+ CD133+ EVs were significantly higher in those with steatohepatitis compare to those with simple steatosis (286.4 ± 61.9 vs 758.4 ± 82.3; p < 0.001). Patients with ballooning 367 ± 40.6 vs 532.0 ± 45.1; p = 0.01 and lobular inflammation (321.1 ± 74.1 vs 721.4 ± 80.1; p = 0.001), showed higher levels of these EVs. These findings were replicated in an independent cohort. CONCLUSIONS: Circulating levels of EpCAM+ CD133+ MVs in clinical and experimental NAFLD were increased in the presence of steatohepatitis, showing high potential as a non-invasive biomarker for the evaluation and management of these patients.

Genetic alterations shaping tumor response to anti-EGFR therapies.

The Epidermal Growth Factor Receptor (EGFR) has been targeted through the development of selective tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAb). These molecules have shown effectiveness in a subset of patients with specific genetic alterations (i.e. gain-of-function EGFR mutations or EGFR gene amplification) and have been approved for their use in non-small-cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic cancer and head and neck cancer. In addition, extensive research is being performed in many other tumour types hoping for a future approval. However, the majority of the patients show no benefit from these molecules due to primary mechanisms of resistance, already present before treatment or show disease progression upon the acquisition of drug resistance mechanisms during the treatment. At present, the majority of patients display resistance due to alterations in genes related to the EGFR signalling pathway that eventually circumvent EGFR inhibition and allow cancer progression. Thus, in this review article we focus on the molecular mechanisms underlying drug resistance via genetic alterations leading to resistance to all anti-EGFR drugs approved by the FDA and/or EMA. We also discuss novel approaches to surmount these chemoresistance modalities.

Zinc Finger E-Box Binding Homeobox 1 Promotes Cholangiocarcinoma Progression Through Tumor Dedifferentiation and Tumor-Stroma Paracrine Signaling.

BACKGROUND AND AIMS: Zinc finger E-box binding homeobox 1 (ZEB1) is a transcription factor that promotes metastatic and stem cell features, which has been associated with poor prognosis in cholangiocarcinoma (CCA), a desmoplastic cancer enriched in cancer-associated fibroblasts (CAFs). We aimed to define ZEB1 regulatory functions in malignant and stromal compartments of CCA. APPROACH AND RESULTS: Bioinformatic and immunohistochemical analyses were performed to determine correlations between ZEB1 and markers of progressiveness in human intrahepatic CCA (iCCA). Gain-of-function and loss-of-function models were generated in CCA cells and liver myofibroblasts as a model of CAFs. Conditioned media (CM) was used to unravel tumor-stroma interplay. In vivo experiments were performed using a xenograft CCA model. ZEB1 expression in tumor cells of human iCCA was associated with undifferentiated tumor and vascular invasion. In vitro, ZEB1 promoted epithelial-mesenchymal transition and stemness in tumor cells, leading to cell migration and spheroid formation. In vivo, ZEB1-overexpressing CCA cells formed larger tumors with more abundant stroma. Expression of cellular communication network factor 2 (CCN2, encoding connective tissue growth factor [CTGF]) was increased in tumor cells from ZEB1-overexpressing xenografts and correlated with ZEB1 expression in human tumors. In vitro, CM from ZEB1-overexpressing tumor cells or recombinant CTGF induced myofibroblast proliferation. ZEB1 was also expressed by CAFs in human CCA, and its expression correlated with CCN2 in myofibroblasts and CCA stroma. In mice, cotransplantation of CCA cells with ZEB1-depleted myofibroblasts reduced CCA progressiveness compared to CCA cells/ZEB1-expressing myofibroblasts. Furthermore, ZEB1 controls the expression of paracrine signals (i.e., HGF and IL6) in tumor cells and myofibroblasts. CONCLUSIONS: ZEB1 plays a key role in CCA progression by regulating tumor cell-CAF crosstalk, leading to tumor dedifferentiation and CAF activation.

Metabolic-associated fatty liver disease: From simple steatosis toward liver cirrhosis and potential complications. Proceedings of the Third Translational Hepatology Meeting, organized by the Spanish Association for the Study of the Liver (AEEH).

This is a meeting report of the 3rd Translational Hepatology Meeting held in Alicante, Spain, in October 2021. The meeting, which was organized by the Spanish Association for the Study of the Liver (AEEH), provided an update on the recent advances in the field of basic and translational hepatology, with a particular focus on the molecular and cellular mechanisms and therapeutic targets involved in metabolic-associated fatty liver disease (MAFLD), metabolic-associated steatohepatitis (MASH), cirrhosis and end-stage hepatocellular carcinoma (HCC).

Technique tip: 3D printing surgical guide for pes cavus midfoot osteotomy.

BACKGROUND: Pes cavus can be defined as an abnormal elevation of the longitudinal arches, which is often secondary to a muscle imbalance. This deformity affects the foot's three dimensions (3D) and our osteotomies are usually planned on a lateral (two-dimension) X-ray. Are we really considering all the spatial components of the deformity? The aim of this study is to present a technique tip to identify the apical plane of the pes cavus deformity and perform a midfoot dorsal-based wedge resection osteotomy by using customized 3D printed surgical guides. METHODS: Three patients underwent the presented technique, all for the indication of symptomatic neuromuscular pes cavus with both anterior and posterior deformity. RESULTS: 3D-printed patient-specific guides help the surgeon to minimize human error, improving intraoperative accuracy, while reducing surgical time and intraoperative X-ray exposure. CONCLUSIONS: Closing wedge midfoot osteotomy to correct anterior pes cavus may be an interesting indication to use customized 3D printed surgical guides.

Ultrasound-guided distal minimally invasive metatarsal osteotomies (US-DMMO): A cadaveric study about its safety and accuracy.

BACKGROUND: Distal minimally invasive metatarsal osteotomies have become increasingly popular. This technique requires fluoroscopic control, but recently, an ultrasound-guided procedure has been described. The aim of this anatomical study was to assess the quality safety of ultrasound-guided minimally invasive metatarsal osteotomies. METHODS: Ultrasound-guided distal minimally invasive metatarsal osteotomies were performed in 9 cadaveric pieces. The location of the osteotomy, its angulation, and the adjacent anatomical structures injuries was evaluated RESULTS: Thirty-six osteotomies were performed. The osteotomy was metaphyseal in 97.2% of the cases, the average angulation was 47.67° (±4.49, 40-59°) and the average distance to the articular cartilage was 3.22 mm (±1.27, 1-7 mm). One osteotomy (2.8%) was intraarticular and there was one joint capsule lesion (2.8%). The failure, the extreme point distance and angulation values, and the joint capsule injury correspond to a fifth metatarsal. CONCLUSIONS: The ultrasound-guided technique is safe and allows a correct location and angulation of the osteotomies.

Tips, quips and pearls: Ultrasound-guided distal metatarsal minimal invasive osteotomy (US-DMMO).

Metatarsalgia is a frequent cause of forefoot pain. Surgical treatment is based on the performance of osteotomies at the level of the minor radii to restore a normal distribution of pressure within the forefoot and improve the biomechanics during gait. In recent years, percutaneous surgery of the foot, and specifically distal metatarsal minimal invasive osteotomy, have proven to be a valid technique, providing satisfactory clinical results, similar to open osteotomy with less soft tissue aggression, but it requires intraoperative fluoroscopy to be performed. This article will present a modification to guide the procedure by ultrasound providing a new option that eliminates radiation and provides greater portability and accessibility.

Cancer-associated fibroblasts in cholangiocarcinoma.

PURPOSE OF REVIEW: To give a state-of-art knowledge regarding cancer-associated fibroblasts (CAF) in cholangiocarcinoma (CCA) based both on direct evidence and studies on other desmoplastic cancers. High contingency of CAF characterizes CCA, a tumor with a biliary epithelial phenotype that can emerge anywhere in the biliary tree. Current treatments are very limited, the surgical resection being the only effective treatment but restricted to a minority of patients, whereas the remaining patients undergo palliative chemotherapy regimens. In cancer, CAF shape the tumor microenvironment, drive cancer growth and progression, and contribute to drug resistance. All these functions are accomplished through an interplay network between CAF and surrounding cells including tumor and other stromal cells, i.e. immune and endothelial cells. RECENT FINDINGS: Several studies have pointed out the existence of CAF sub-populations carrying out several and opposite functions, cancer-promoting or cancer-restraining as shown in pancreatic cancer, another prototypic desmoplastic tumor in which heterogeneity of CAF is well demonstrated. SUMMARY: New CAF functions are now emerging in pancreatic and breast cancers like the modulation of immune responses or tumor metabolism, opening new area for treatments.

Is Dual Antibiotic-Loaded Bone Cement More Effective and Cost-Efficient Than a Single Antibiotic-Loaded Bone Cement to Reduce the Risk of Prosthetic Joint Infection in Aseptic Revision Knee Arthroplasty?

BACKGROUND: Higher rates of prosthetic joint infections (PJIs) are related to patient risk factors and/or to special surgical procedures such as revision total knee arthroplasty (rTKA). Among the measures discussed to better protect those patients from the higher infection risks use of dual antibiotic-loaded bone cement has emerged as a further prophylactic option. METHODS: This retrospective study included 246 patients undergoing strictly aseptic revision knee arthroplasty at our institution in the time period 2015-2018. Based on the type of bone cement used for the cementation of the revision prosthesis, 2 groups were defined. In total, 143 patients received the low-dose single antibiotic-loaded bone cement (SALBC) PALACOS R+G and 103 patients received the high-dose dual antibiotic-loaded bone cement (DALBC) COPAL G+C. The number of PJI cases in each group over a follow-up time of minimum 1 year was compared and the extra costs for the DALBC use calculated against the economic savings per each avoided PJI case on basis of 3 different assumptions (treatment costs and amount of cement use). RESULTS: Use of DALBC in aseptic rTKA was associated with a significant reduction in PJI cases (relative risk = 57%, PJI rate in the SALBC group 4.1% vs 0% in the DALBC group, P = 0.035). The calculated total savings per patient was $1367. Depending on the economic assumptions the range of savings was between $1413 (less favorable calculation model) and $3661 (most favorable calculation model). CONCLUSION: The use of DALBC in rTKA has been found to be more effective in preventing PJI and proved cost-efficient in all our cost-calculation models.

Retrograde Tibial Nail and Trabecular Titanium Spacer Block for the Treatment of Missing Talus: A Rare Case Report.

Astragalus enucleation with complete bone loss is a rare pathology, and there is no current classification or treatment protocol. A 34-year-old woman sustained an open total enucleation of the talus without bone recovery in a motorcycle accident. Initially, she was treated at the emergency department with wound cleaning, surgical debridement, and external fixation with intravenous antibiotic therapy. Definitive treatment was delayed 8 weeks because of acute infection, which was treated with lavage, surgical debridement, and specific antibiotic therapy. To avoid leg-length discrepancy, we performed a tibiocalcaneal arthrodesis using a trabecular titanium spacer block with retrograde intramedullary nailing. We report satisfactory clinical, functional, and radiological results at 24 months after surgery. No complications or dysmetria was reported. The treatment of choice after an open talar enucleation with bone loss is the tibiocalcaneal arthrodesis, and it can be done isolated or with an associated autologous bone graft or allograft. The most frequent complications are infection, pseudoarthrosis, and, if the talar space is not adequately filled, dysmetria. We present a new way of filling this defect, which is not described in the current literature, using a trabecular titanium spacer block (indicated for revision of ankle arthrodesis of the hindfoot) together with retrograde intramedullary nailing, with promising results.

Does the minimally invasive complete plantar fasciotomy result in deformity of the Plantar arch? A prospective study.

BACKGROUND: Complete plantar fasciotomy has been associated with changes in foot loading, leading to medial longitudinal arch collapse. The purpose of this study is to analyse our clinical experience with percutaneous complete plantar fasciotomy and quantify the possible changes in foot loading measured by the calcaneal pitch angle. METHODS: A prospective case series study with patients operated between 2005-2012 was conducted, where AOFAS, Maryland Foot Score (MFS), VAS and radiological calcaneal pitch (CP) were recorded. Postoperative data were collected, where the surgeon evaluated the presence of complications, and an independent investigator performed radiological and scale evaluations follow-up: AOFAS, MFS, VAS and Benton-Weil questionnaire. RESULTS: A total of 60 patients, 62 feet, with a mean follow-up of 57 months (range 13-107) were studied. The MFS increased a mean of 21 points (p=.001), the AOFAS score a mean of 25 points (p=.001), and the VAS decreased a mean of 8.89 points (p=.001). A total of fifty-seven feet (91.9%) were pain-free at the end of follow-up. The mean CP dropped from 20.2° (range 11-34) preoperatively to 19.3° (range 11-34) at the end of follow-up (p=.05). In 25 feet (40.3%) there were no changes in the calcaneus pitch angle, in 21 feet dropped 1° (33.9%), in 11 dropped 2° (17.8%), 3 feet 3° (4.8%) and 2 feet (3.2%) 4°. Postoperative complications were noted in 4 feet (6.4%), with lateral column pain. The surgery meets the expectations of all patients. CONCLUSIONS: Percutaneous total fascia release is safe and does not produce a significant drop in arch height based on the radiological finding. Lack of success after surgery may be explained by other pathologies that might appear like plantar fasciitis. Further studies with gait analysis after total plantar fascia release in patients are needed.

Gene expression, protein profiling, and chemotactic activity of infrapatellar fat pad mesenchymal stem cells in pathologies of the knee joint.

The infrapatellar fat pad (IPFP) is a periarticular adipose knee tissue. This tissue contains a large number of mesenchymal stem cells (MSCs). In the present work, we wanted to study the IPFP MSCs and their relationship and differences in two groups, anterior cruciate ligament (ACL) ruptures knees and ostheoarthrosis (OA). The IPFP of 42 patients with OA or ACL rupture were analyzed. Isolation, primary culture, and a genetic and proteomic study of MSCs from IPFP were performed. Gene expression of IL-6, tumor necrosis factor (TNF), IL-8, HSPA1A (Hsp70), CXCL10, RANTES, MMP1, MMP3, TIMP1, and BMP7 was analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). We analyzed MSCs from from 12 diferents patients in two cellular pools (6 from AO disease and 6 from ALC rupture to form two cell pool), for the iTRAQ Proteomic Assay. The conditional media were used in quantitative analysis of MSC soluble factors by Luminex and for de migration assay. A higher gene expression of IL-6, TNF, CXCL10, RANTES, and MMP1 and OPG in MSCs from OA versus ACL (p < 0.05) was observed. Conversely HSPA1A, TIMP1, and RANKL showed a significant lower expression in OA-MSCs (p < 0.05). In the secretome analysis, adipsin and visfantin levels in the supernatants from OA-MSCs were lower (p < 0.05) respect to ACL-MSCs. Also, the monocytic cells migrated two-folds in the presence of conditioned media from OA-MSCs patients versus patients with ACL-MSC. The infrapatellar pad should be considered as an adipose tissue capable of producing and excreting inflammatory mediators directly in the knee joint, influencing the development and progression of knee joint pathologies.

Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology.

The ErbB/HER family comprises four distinct tyrosine kinase receptors, EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4, which trigger intracellular signals at the origin of essential cellular functions, including differentiation, proliferation, survival, and migration. Epithelial cells, named cholangiocytes, that line intrahepatic and extrahepatic bile ducts, contribute substantially to biliary secretory functions and bile transport. Although ErbB receptors have been widely studied in cholangiocarcinoma (CCA), a malignancy of the biliary tract, knowledge of these receptors in biliary epithelium physiology and in non-malignant cholangiopathies is far from complete. Current knowledge suggests a role for epidermal growth factor receptor (EGFR) in cholangiocyte specification and proliferation, and in hepatocyte transdifferentiation into cholangiocytes during liver regeneration to restore biliary epithelium integrity. High expression and activation of EGFR and/or ErbB2 were recently demonstrated in biliary lithiasis and primary sclerosing cholangitis, two cholangiopathies regarded as risk factors for CCA. In CCA, ErbB receptors are frequently overexpressed, leading to tumor progression and low prognosis. Anti-ErbB therapies were efficient only in preclinical trials and have suggested the existence of resistance mechanisms with the need to identify predictive factors of therapy response. This review aims to compile the current knowledge on the functions of ErbB receptors in physiology and physiopathology of the biliary epithelium. (Hepatology 2018;67:762-773).

MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although its etiopathogenesis remains obscure, development of antimitochondrial autoantibodies against pyruvate dehydrogenase complex E2 is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but its functional relevance is largely unknown. We previously reported that miR-506 is overexpressed in PBC cholangiocytes and directly targets both Cl- / HCO3- anion exchanger 2 and type III inositol 1,4,5-trisphosphate receptor, leading to cholestasis. Here, the regulation of miR-506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several proinflammatory cytokines overexpressed in PBC livers (such as interleukin-8 [IL8], IL12, IL17, IL18, and tumor necrosis factor alpha) stimulated miR-506 promoter activity in human cholangiocytes, as revealed by luciferase reporter assays. Experimental overexpression of miR-506 in cholangiocytes dysregulated the cell proteomic profile (by mass spectrometry), affecting proteins involved in different biological processes including mitochondrial metabolism. In cholangiocytes, miR-506 (1) induced dedifferentiation with down-regulation of biliary and epithelial markers together with up-regulation of mesenchymal, proinflammatory, and profibrotic markers; (2) impaired cell proliferation and adhesion; (3) increased oxidative and endoplasmic reticulum stress; (4) caused DNA damage; and (5) sensitized to caspase-3-dependent apoptosis induced by cytotoxic bile acids. These events were also associated with impaired energy metabolism in mitochondria (proton leak and less adenosine triphosphate production) and pyruvate dehydrogenase complex E2 overexpression. Coculture of miR-506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. CONCLUSION: Different proinflammatory cytokines enhance the expression of miR-506 in biliary epithelial cells; miR-506 induces PBC-like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients. (Hepatology 2018;67:1420-1440).

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance.

Cholangiocarcinoma (CCA) is a deadly disease. While surgery may attain cure in a minor fraction of cases, therapeutic options in either the adjuvant or advanced setting are limited. The possibility of advancing the efficacy of therapeutic approaches to CCA relies on understanding its molecular pathogenesis and developing rational therapies aimed at interfering with oncogenic signalling networks that drive and sustain cholangiocarcinogenesis. These efforts are complicated by the intricate biology of CCA, which integrates not only the driving force of tumour cell-intrinsic alterations at the genetic and epigenetic level but also pro-tumorigenic cues conveyed to CCA cells by different cell types present in the rich tumour stroma. Herein, we review our current understanding of the mechanistic bases underpinning the activation of major oncogenic pathways causative of CCA pathogenesis. We subsequently discuss how this knowledge is being exploited to implement rationale-based and genotype-matched therapeutic approaches that predictably will radically transform CCA clinical management in the next decade. We conclude by highlighting the mechanisms of therapeutic resistance in CCA and reviewing innovative approaches to combat resistance at the preclinical and clinical level.

Enoxaparin does not ameliorate liver fibrosis or portal hypertension in rats with advanced cirrhosis.

BACKGROUND & AIMS: Recent studies suggest that heparins reduce liver fibrosis and the risk of decompensation of liver disease. Here, we evaluated the effects of enoxaparin in several experimental models of advanced cirrhosis. METHODS: Cirrhosis was induced in male Sprague-Dawley (SD) rats by: (i) Oral gavage with carbon tetrachloride (CCl4ORAL ), (ii) Bile duct ligation (BDL) and (iii) CCl4 inhalation (CCl4INH ). Rats received saline or enoxaparin s.c. (40 IU/Kg/d or 180 IU/Kg/d) following various protocols. Blood biochemical parameters, liver fibrosis, endothelium- and fibrosis-related genes, portal pressure, splenomegaly, bacterial translocation, systemic inflammation and survival were evaluated. Endothelial dysfunction was assessed by in situ bivascular liver perfusions. RESULTS: Enoxaparin did not ameliorate liver function, liver fibrosis, profibrogenic gene expression, portal hypertension, splenomegaly, ascites development and infection, serum IL-6 levels or survival in rats with CCl4ORAL or BDL-induced cirrhosis. Contrarily, enoxaparin worsened portal pressure in BDL rats and decreased survival in CCl4ORAL rats. In CCl4INH rats, enoxaparin had no effects on hepatic endothelial dysfunction, except for correcting the hepatic arterial dysfunction when enoxaparin was started with the CCl4 exposure. In these rats, however, enoxaparin increased liver fibrosis and the absolute values of portal venous and sinusoidal resistance. CONCLUSIONS: Our results do not support a role of enoxaparin for improving liver fibrosis, portal hypertension or endothelial dysfunction in active disease at advanced stages of cirrhosis. These disease-related factors and the possibility of a limited therapeutic window should be considered in future studies evaluating the use of anticoagulants in cirrhosis.

Clinical and radiological outcomes of trabecular metal systems and antiprotrusion cages in acetabular revision surgery with severe defects: a comparative study.

INTRODUCTION: Acetabular revision surgery poses a challenge due to the increased frequency of severe defects and poor quality of the remaining bone. We compare the clinical and radiological outcomes, complications, and survival of two systems commonly used in complex acetabular revisions (AAOS types II, III, and IV): trabecular metal system (TM) and Burch-Schneider antiprotrusion cages (BS). METHODS: Eighty-four patients underwent acetabular revision surgery with TM or BS in our centre between 2008 and 2014. Comparison was made of demographic and clinical characteristics, satisfaction, radiographic parameters, complications, and survival of the implants. A BS was implanted in 30.9% of the patients, while 69.1% received a TM implant. The mean follow-up was 4.77 years. RESULTS: The BS group required a significantly greater number of constrained implants (p = 0.001) and more walking aids (p = 0.04). The mean satisfaction (p = 0.02) and HHS scores at the end of the follow-up were higher in the TM group (p = 0.003). No differences were observed in the incidence of complications, though the only two cases of implant rupture corresponded to the BS group. The overall survival rate was 88.1% after 7.5 years. CONCLUSION: TM implants afforded better clinical outcomes and greater patient satisfaction than antiprotrusion cages in the treatment of severe acetabular defects.