Intermediate-advanced hepatocellular carcinoma in Argentina:Treatment and survival analysis

BACKGROUND Hepatocellular carcinoma(HCC) represents the sixteenth most frequent cancer in Argentina. The rise of new therapeutic modalities in intermediate-advanced HCC opens up a new paradigm for the treatment of HCC.AIM To describe real-life treatments performed in patients with intermediateadvanced HCC before the approval of new systemic options.METHODS This longitudinal observational cohort study was conducted between 2009 and2016 in 14 different regional hospitals from Argentina. Included subjects had intermediate-advanced Barcelona Clinic Liver Cancer(BCLC) HCC stages(BCLC B to D). Primary end point analyzed was survival, which was assessed for each BCLC stage from the date of treatment until last patient follow-up or death.Kaplan Meier survival curves and Cox regression analysis were performed, with hazard ratios(HR) calculations and 95% confidence intervals(95%CI).RESULTS From 327 HCC patients, 41% were BCLC stage B, 20% stage C and 39% stage D.Corresponding median survival were 15 mo(IQR 5-26 mo), 5 mo(IQR 2-13 mo)and 3 mo(IQR 1-13 mo)(P < 0.0001), respectively. Among BCLC-B patients(n =135), 57% received TACE with a median number of 2 sessions(IQR 1-3 sessions).Survival was significantly better in BCLC-B patients treated with TACE HR =0.29(CI: 0.21-0.40) than those without TACE. After tumor reassessment by RECIST 1.1 criteria following the first TACE, patients with complete response achieved longer survival (HR = 0.15(CI: 0.04-0.56, P = 0.005))Eighty-two patients were treated with sorafenib, mostly BCLC-B and C(87.8%). However,12.2% were BCLC-D. Median survival with sorafenib was 4.5 mo(IQR 2.3-11.7 mo);which was lower among BCLC-D patients 3.2 mo(IQR 2.0-14.1 mo). A total of 36 BCLC-B patients presented tumor progression after TACE. In these patients,treatment with sorafenib presented better survival when compared to those patients who received sorafenib without prior TACE [HR = 0.26(CI: 0.09-0.71);P= 0.013].CONCLUSION In this real setting, our results were lower than expected. This highlights unmet needs in Argentina, prior to the introduction of new treatments for HCC.

Checkpoint inhibitor-induced hepatotoxicity:Role of liver biopsy and management approach

Immunological checkpoint inhibitors(ICIs)have revolutionized therapy of many different malignanices.Concomitant immune-mediated adverse effects are common and can affect many organs such as the skin,lungs,gastrointestinal and endocrine organs as well as the liver.Liver injury has been reported in 3%-8%of patients with grade III-IV hepatitis in retrospective studies.The liver injury is characterized by hepatocellular injury resembling autoimmune hepatitis biochemically but not immunologically as patients with ICI induced hepatoxicity rarely have auto-antibodies or IgG elevation.The role for liver biopsy(LB)in patients with suspected liver injury due to ICIs is controversial and it is not clear whether results of a LB will change clinical management.LB can be helpful when there is diagnostic uncertainty and pre-existing liver disease is suspected.Although there are no distinctive histological features,the finding of granulomas and endothelitis may suggest a specific type of hepatitis induced by ICIs.The natural history of hepatotoxicity of ICI therapy is not well known.Recent studies have demonstrated that 33%-50%of patients improve spontaneously with discontinuation of ICIs.In patients with jaundice and/or coagulopathy corticosteroids are used.The high doses of corticosteroids with 1-2 mg/kg/d of methylprednisolone recommended by the oncological societies are controversial.Recently it has shown that initial treatment with 1 mg/kg/d provided similar liver tests improvement which was also associated with a reduced risk of steroid-induced adverse effects in comparison with higher-dose regimens.Secondary immunosuppression mostly with mycophenolate mofetil has been reported to be helpful.

Dome-Shaped Macula and Foveal Neurosensory Retinal Detachment—A Case Series

Objective: To report a case series of dome-shaped macula (DSM) and serous retinal detachment (SRD). Methods: A retrospective and observational case series study was performed at two centers of ophthalmology in Rosario-Argentina from January 2016 to December 2017. Eight eyes of 5 patients diagnosed with dome-shaped macula with subfoveal hyporeflective zone seen in optical coherence tomography (OCT) were included. Best-corrected visual acuity (BCVA), OCT, fluorescein angiography (FA), differential diagnoses, clinical course and different treatments were reviewed. Results: Baseline visual acuity ranged from 20/25 to 20/200. OCT revealed that the retinal choroidal macular complex had a convex shape and exhibited foveal neurosensory retinal detachment in all cases. FA showed mild diffuse hyperfluorescence due to changes in the retinal pigment epithelium (RPE). No sign of leakage was observed. Different treatments were used, including intravitreal antiangiogenic drugs, oral spironolactone, melatonin and observation. Follow-up time was between 6 and 18 months. BCVA and OCT findings remained unchanged after different options of treatment. Conclusions: DSM is an unusual entity, which can be confused with other maculopathies that cause neurosensory retinal detachment and do not respond to different types of treatment. Hence, in our opinion, observation is a reasonable approach for this disorder.

Overview on drug-induced liver injury in Brazil

Drug-induced liver injury(DILI)is an uncommon event in clinical practice,which makes knowing its true incidence difficult.Prospective,retrospective and registry-based studies are the most important methods to obtain epidemiological data on DILI.Latin America(LA)has a historical lack of prospective studies on this topic.New definitions and the creation of hepatotoxicity registries have significantly improved the epidemiological understanding of hepatic drug reactions in several regions of the world.The Latin American DILI network,referred to as LATINDILI,has been created in 2011,and recently published its own DILI recommendations describing the most relevant issues on the management of hepatotoxicity in general,and those based on findings from our own LA experience in particular.Although most of the registries do not carry out population-based studies,they may provide important data related to the prevalence of DILI.The joint work among researchers and the corresponding health and regulatory authorities should be stimulated due to the high impact that hepatotoxicity represents for public health.

Hepatotoxicity Induced by Biological Agents: Clinical Features and Current Controversies

Novel biological agents including cytokines and recombinant fusion proteins are increasingly prescribed for cancer,rheumatologic,autoimmune,and inflammatory diseases,and are currently being evaluated in hepatocellular carcinoma(HCC).They are classified by their mechanism of action and include tumor necrosis factor-alpha(TNF-α)antagonists,T cell mediated antitumor inhibitors,interleukin receptor antagonists,and immune checkpoint inhibitors(ICIs).Some ICIs cause frequent hepatotoxicity with a variable clinical,biochemical,and serological presentation,especially in patients receiving another immunomodulatory agent.Half of the cases of liver damage induced by biological agents spontaneously regress after drug withdrawal,but the others require steroid therapy.Unfortunately,there are no widely accepted recommendation for the use of corticosteroids in these patients,even though international cancer societies have their own guidelines.Differentiating drug-induced autoimmune hepatitis(DIAIH)from classic AIH is challenging for pathologists,but liver biopsy is valuable,particularly in cases with unclear clinical presentation.Interesting,novel histological patterns have been described in liver damage induced by these agents(i.e.,endothelitis,ring granuloma and secundary sclerosing cholangitis associated with lymphocytic infiltration of cytotoxic CD8+T cells).Here,we describe the clinical and biochemical characteristics of patients with hepatotoxicity induced by TNF-αantagonists and ICIs.Controversial issues involved in the administration of corticosteroid therapy,and hepatitis B virus(HBV)reactivation induced by immunosuppressive therapy are also discussed.