Glioblastoma Multiforme (GBM) is still an incurable disease. The front-line Temozolomide (TMZ)-based therapy suffers from poor efficacy, underlining the need of new therapies. Preclinically, ...Aldoxorubicin (Aldox), a novel prodrug of Doxorubicin (Dox), has been successfully tested against GBM, encouraging the study of its association with other agents. For the first time, we evaluated the effectiveness of Aldox combined to TMZ in preclinical models of GBM. Our
results demonstrated that the anti-glioma effect of Aldox was more marked than TMZ and their combination increased the killing effect of the anthracycline in TMZ-resistant GBM cells. Moreover, unlike Dox, Aldox was able to accumulate in P-glycoprotein (P-gp)-overexpressed cells due to a negative regulation of the P-gp function. We also compared efficacy and safety of weekly administrations of Aldox (16 mg/kg), with or without TMZ (0.9 mg/kg, daily injections), in the U87 xenograft mouse model. Aldox therapy induced a moderate tumor volume inhibition (TVI) and an increased survival rate (+12.5%
vehicle). On the other hand, when combined to TMZ, Aldox caused a significant TVI (P=0.0175
vehicle) and delayed the mortality during the experimental period, although TVI and endpoint survival percentage (+37.5%
vehicle) were not significantly different from TMZ alone. Our preliminary data showed that Aldox exerts anti-glioma effects
and
. It also enhances its antitumor activity when combined with TMZ, resulting in a superior efficacy compared to the single agents, without adverse side effects.
Type‐2 diabetes mellitus is a frequent comorbidity of cirrhosis independently associated with cirrhosis‐related complications and mortality. This post hoc analysis of the ANSWER trial database ...assessed the effects of long‐term human albumin (HA) administration on top of the standard medical treatment (SMT) on the clinical outcomes of a subgroup of 85 outpatients with liver cirrhosis, uncomplicated ascites and insulin‐treated diabetes mellitus type 2 (ITDM). Compared to patients in the SMT arm, the SMT + HA group showed a better overall survival (86% vs. 57%, p = .016) and lower incidence rates of paracenteses, overt hepatic encephalopathy, bacterial infections, renal dysfunction and electrolyte disorders. Hospital admissions did not differ between the two arms, but the number of days spent in hospital was lower in the SMT + HA group. In conclusion, in a subgroup of ITDM outpatients with decompensated cirrhosis and ascites, long‐term HA administration was associated with better survival and a lower incidence of cirrhosis‐related complications.
Abstract Background Liver stiffness has been suggested as a parameter of fibrosis progression/regression in hepatitis C virus (HCV) patients. Aim To evaluate stiffness before and after ...peginterferon–ribavirin treatment. Methods Stiffness was prospectively measured in 74 HCV patients, 32 genotypes 1/4 (43.25%) and 42 genotypes 2/3 (56.75%), before, at end of treatment, and after 3 years of follow-up (49 patients). On the same study day, 21 patients underwent liver biopsy. Results In 55 patients with sustained virological response (74.32%), liver stiffness decreased significantly at end of therapy (6.8 ± 4.9 kPa) vs. baseline (9.5 ± 6.9 kPa, p = 0.04). The decrease vs. baseline was maintained in 30 sustained virological response patients after 3 years follow-up (6.8 ± 4.6 kPa vs. 10.8 ± 8.5 kPa, p = 0.0141). No difference was found at end of treatment vs. baseline (10.1 ± 4.7 kPa vs. 9.7 ± 4.2 kPa, p = 0.825) and after 3 years of follow-up vs. baseline (10.2 ± 3.4 kPa vs. 9.7 ± 4.2 kPa, p = 0.765) in null responders. Similar results were found in relapsers at end of treatment vs. baseline (13.7 ± 7.7 kPa vs. 15.2 ± 8.2 kPa, p = 0.74), and after 3 years of follow-up vs. baseline (16.9 ± 10.0 kPa vs. 15.2 ± 8.2 kPa, p = 0.734). Pre-treatment stiffness >12 kPa was significantly associated with no SVR ( p < 0.025), RR = 2.44 (95% C.I. 1.17–5.07). Conclusion Liver stiffness may be useful to assess long-term antiviral treatment response.
Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The ...aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-kappaB. Resistin induced a rapid increase in intracellular calcium concentration, mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-kappaB activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca2+/NF-kappaB-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis.
This study investigated how material deprivation in Italy influences the stage of hepatocellular carcinoma (HCC) at diagnosis and the chance of cure.
4114 patients from the Italian Liver Cancer ...database consecutively diagnosed with HCC between January 2008 and December 2018 were analysed about severe material deprivation (SMD) rate tertiles of the region of birth and region of managing hospitals, according to the European Statistics on Income and Living Conditions. The main outcomes were HCC diagnosis modalities (during or outside surveillance), treatment adoption and overall survival.
In more deprived regions, HCC was more frequently diagnosed during surveillance, while the incidental diagnosis was prevalent in the least deprived. Tumour characteristics did not differ among regions. The proportion of patients undergoing potentially curative treatments progressively decreased as the SMD worsened. Consequently, overall survival was better in less deprived regions. Patients who moved from most deprived to less deprived regions increased their probability of receiving potentially curative treatments by 1.11 times (95% CI 1.03 to 1.19), decreasing their mortality likelihood (hazard ratio 0.78 95% CI 0.67 to 0.90).
Socioeconomic status measured through SMD does not seem to influence HCC features at diagnosis but brings a negative effect on the chance of receiving potentially curative treatments. Patient mobility from the most deprived to the less deprived regions increased the access to curative therapies, with the ultimate result of improving survival.
•A Multicentre Italian study on the impact of material deprivation on hepatocellular carcinoma (HCC) outcome.•Patients were stratified according to the material deprivation rate of Italian regions.•HCC survival was better in less deprived Italian regions.•Migration from most to less deprived regions improved HCC survival.•Effect of deprivation was mainly because of different access to HCC curative treatments.
We reported a female patient with unrecognized celiac disease and multiple extra intestinal manifestations, mainly related to a deranged immune function, including macroamilasemia, macrolipasemia, ...IgA nephropathy,thyroiditis, and anti-b2-glicoprotein-1 antibodies, that disappeared or improved after the implementation of a gluten-free diet.
Portal vein thrombosis may occur in cirrhosis; nevertheless, its prevalence, and predictors are still elusive. To investigate this issue, the Italian Society of Internal Medicine undertook the ...“Portal vein thrombosis Relevance On Liver cirrhosis: Italian Venous thrombotic Events Registry” (PRO-LIVER). This prospective multicenter study includes consecutive cirrhotic patients undergoing Doppler ultrasound examination of the portal area to evaluate the prevalence and incidence of portal vein thrombosis over a 2-year scheduled follow-up. Seven hundred and fifty-three (68 % men; 64 ± 12 years) patients were included in the present analysis. Fifty percent of the cases were cirrhotic outpatients. Viral (44 %) etiology was predominant. Around half of the patients had a mild-severity disease according to the Child–Pugh score; hepatocellular carcinoma was present in 20 %. The prevalence of ultrasound-detected portal vein thrombosis was 17 % (
n
= 126); it was asymptomatic in 43 % of the cases. Notably, more than half of the portal vein thrombosis patients (
n
= 81) were not treated with anticoagulant therapy. Logistic step-forward multivariate analysis demonstrated that previous portal vein thrombosis (
p
< 0.001), Child–Pugh Class B + C (
p
< 0.001), hepatocellular carcinoma (
p
= 0.01), previous upper gastrointestinal bleeding (
p
= 0.030) and older age (
p
= 0.012) were independently associated with portal vein thrombosis. Portal vein thrombosis is a frequent complication of cirrhosis, particularly in patients with moderate–severe liver failure. The apparent undertreatment of patients with portal vein thrombosis is a matter of concern and debate, which should be addressed by planning interventional trials especially with newer oral anticoagulants.
Clinicaltrials.gov identifier
NCT01470547.
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