Drop-out rate from the liver transplant waiting list due to HCC progression in HCV-infected patients treated with direct acting antivirals.

BACKGROUND & AIM: concerns about an increased hepatocellular carcinoma (HCC) recurrence rate following directly acting antiviral (DAA) therapy in cirrhotic patients with a prior complete oncological response have been raised. Data regarding the impact of HCV-treatment with DAAs on waiting list drop-out rates in patients with active HCC and HCV-related cirrhosis awaiting liver transplantation (LT) are lacking. MATERIALS AND METHODS: HCV-HCC patients listed for LT between January 2015 and May 2016 at Padua Liver Transplant Centre were considered eligible for the study. After enrollment patients were divided into 2 groups, depending on whether they underwent DAAs treatment while awaiting LT or not. For each patient clinical, serological and virological data were collected. HCC characteristics were radiologically evaluated at baseline and during follow-up (FU). For transplanted patients, pathological assessment of the explants was performed and recurrence-rates were calculated. RESULTS: twenty-three patients treated with DAAs and 23 controls were enrolled. HCC characteristics at time of LT-listing were comparable between the 2 groups. Median FU was 10 and 7 months, respectively, during which 2/23 (8.7%) and 1/23 (4.3%) drop-out events due to HCC-progression were registered (p = 0.9). No significant differences in terms of radiological progression were highlighted (p = 0.16). Nine out of 23 cases (39%) and 14/23 (61%) controls underwent LT, and histopathological analysis showed no differences in terms of median number and total tumor volume of HCC nodules, tumor differentiation or microvascular invasion. During post-LT FU, 1/8 DAAs treated patient (12,5%) and 1/12 control (8,3%) experienced HCC recurrence (p = 0.6). CONCLUSIONS: Viral eradication does not seem to be associated with an increased risk of drop-out due to neoplastic progression in HCV-HCC patients awaiting LT

Hypercoagulability progresses to hypocoagulability during evolution of acetaminophen-induced acute liver injury in pigs

Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists. This study defines evolution of coagulopathy in 10 pigs with acetaminophen (APAP)-induced ALI compared to 3 Controls. APAP administration began at 0 h and continued to ‘ALF’, defined as INR >3. In APAP pigs, INR was 1.05 ± 0.02 at 0 h, 2.15 ± 0.43 at 16 h and > 3 at 18 ± 1 h. At 12 h thromboelastography (TEG) demonstrated increased clot formation rate, associated with portal vein platelet aggregates and reductions in protein C, protein S, antithrombin and A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats–13 (ADAMTS-13) to 60%, 24%, 47% and 32% normal respectively. At 18 ± 1 h, INR > 3 was associated with: hypocoagulable TEG profile with heparin-like effect; falls in thrombin generation, Factor V and Factor VIII to 52%, 19% and 17% normal respectively; further decline in anticoagulants; thrombocytopenia; neutrophilia and endotoxemia. Multivariate analysis, found that ADAMTS-13 was an independent predictor of a hypercoagulable TEG profile and platelet count, endotoxin, Protein C and fibrinogen were independent predictors of a hypocoagulable TEG profile. INR remained normal in Controls. Dynamic changes in coagulation occur with progression of ALI: a pro-thrombotic state progresses to hypocoagulability

Anticoagulant therapy for splanchnic vein thrombosis: an individual patient data meta-analysis

Robust evidence on the optimal management of splanchnic vein thrombosis (SVT) is lacking. We conducted an individual-patient meta-analysis to evaluate the effectiveness and safety of anticoagulation for SVT. Medline, Embase, and clincaltrials.gov were searched up to June 2021 for prospective cohorts or randomized clinical trials including patients with SVT. Data from individual datasets were merged, and any discrepancy with published data was resolved by contacting study authors. Three studies of a total of 1635 patients were included. Eighty-five percent of patients received anticoagulation for a median duration of 316 days (range, 1-730 days). Overall, incidence rates for recurrent venous thromboembolism (VTE), major bleeding, and mortality were 5.3 per 100 patient-years (p-y; 95% confidence interval [CI], 5.1-5.5), 4.4 per 100 p-y (95% CI, 4.2-4.6), and 13.0 per 100 p-y (95% CI, 12.4-13.6), respectively. The incidence rates of all outcomes were lower during anticoagulation and higher after treatment discontinuation or when anticoagulation was not administered. In multivariable analysis, anticoagulant treatment appeared to be associated with a lower risk of recurrent VTE (hazard ratio [HR], 0.42; 95% CI, 0.27-0.64), major bleeding (HR, 0.47; 95% CI, 0.30-0.74), and mortality (HR, 0.23; 95% CI, 0.17-0.31). Results were consistent in patients with cirrhosis, solid cancers, myeloproliferative neoplasms, unprovoked SVT, and SVT associated with transient or persistent nonmalignant risk factors. In patients with SVT, the risk of recurrent VTE and major bleeding is substantial. Anticoagulant treatment is associated with reduced risk of both outcomes. © 2022 by The American Society of Hematology

Aszites, Pfortaderthrombose und hepatische Enzephalopathie bei Leberzirrhose: Aktuelle Therapieempfehlungen

Treatment of Ascites, Portal Vein Thrombosis and Hepatic Encephalopathy in Patients with Cirrhosis of the Liver Background: Ascites, portal vein thrombosis and hepatic encephalopathy are important complications of cirrhosis of the liver. Guidelines for the treatment of ascites have recently been published. Method: This manuscript summarizes up-to-date recommendations on the basis of the DGVS S3 guideline and of other guidelines as well as of the authors' experience. Results and Conclusions: TIPS (transjugular intrahepatic porto-systemic shunt) is the preferred treatment for refractory or recidivant ascites unless there are contraindications. The therapy of hepatorenal syndrome type 1 with albumin and the vasoconstrictor Terlipressin has been proven effective. Treatment of portal vein thrombosis comprises a strategy of anticoagulation, TIPS and liver transplantation. The most important therapeutic strategy for hepatic encephalopathy is the search for as well as the treatment of trigger events. Rifaximin is being increasingly used for the treatment and prophylaxis of hepatic encephalopathy

Molecular Refinement of Clinical Staging in Hepatocellular Carcinoma Patients Evaluated for Potentially Curative Therapies

Abstract: Aim: VEGF and AFP mRNA determinations in the blood are promising prognostic factors for patients with HCC. This study explores their potential prognostic synergy in a cohort of HCC patients evaluated for potentially curative therapies. Methods: One hundred twenty-four patients with a diagnosis of HCC were prospectively enrolled in the study. Inclusion criteria were: (a) histological diagnosis of HCC and assessment of tumour grade and (b) determination of AFP mRNA status and VEGF levels in the blood before therapy. Results: At baseline evaluation, 40% of the study group had AFP mRNA in the blood (AFP mRNA positive), and 35% had VEGF > 23 pg ml(-1) (VEGF positive). Surgery was performed in 58 patients (47%), 54 (43%) had tumour ablation, and 12 had chemoembolisation (10%). Median follow-up and survival of the study group were 19 and 26 months (range, 1 to 60), respectively. The association of AFP mRNA and VEGF proved to be prognostically more accurate than their single use in discriminating the risk of death (ROC curve analysis) and survival probability (Cox analysis). In particular, we identified 3 main molecular stages (p < 0,0001): both negative (3-year survival = 63%), one positive (3-year survival = 40%), both positive (3-year survival = 16%). Multivariate analysis identified BCLC staging, surgery, and molecular staging as the most significant survival variables. Conclusions: The preoperative determination of AFP mRNA status and VEGF may potentially refine the prognostic evaluation of HCC patients and improve the selection process for potentially curative therapies

Sprouted Innervation into Uterine Transplants Contributes to the Development of Hyperalgesia in a Rat Model of Endometriosis

Endometriosis is an enigmatic painful disorder whose pain symptoms remain difficult to alleviate in large part because the disorder is defined by extrauteral endometrial growths whose contribution to pain is poorly understood. A rat model (ENDO) involves autotransplanting on abdominal arteries uterine segments that grow into vascularized cysts that become innervated with sensory and sympathetic fibers. ENDO rats exhibit vaginal hyperalgesia. We used behavioral, physiological, and immunohistochemical methods to test the hypothesis that cyst innervation contributes to the development of this hyperalgesia after transplant. Rudimentary sensory and sympathetic innervation appeared in the cysts at two weeks, sprouted further and more densely into the cyst wall by four weeks, and matured by six weeks post-transplant. Sensory fibers became abnormally functionally active between two and three weeks post-transplant, remaining active thereafter. Vaginal hyperalgesia became significant between four and five weeks post-transplant, and stabilized after six to eight weeks. Removing cysts before they acquired functional innervation prevented vaginal hyperalgesia from developing, whereas sham cyst removal did not. Thus, abnormally-active innervation of ectopic growths occurs before hyperalgesia develops, supporting the hypothesis. These findings suggest that painful endometriosis can be classified as a mixed inflammatory/neuropathic pain condition, which opens new avenues for pain relief. The findings also have implications beyond endometriosis by suggesting that functionality of any transplanted tissue can be influenced by the innervation it acquires