Ischemic preconditioning protects liver from hepatectomy under hepatic inflow occlusion for hepatocellular carcinoma patients with cirrhosis

AIM:To investigate the protective effect of ischernicpreconditioning(IPC)on hepatocellular carcinoma(HCC)patients with cirrhosis undergoing hepatic resection underhepatic inflow occlusion(HIO)and its possible mechanism.METHODS:Twenty-nine consecutive patients with resectable0HCC were randomized into two groups:IPC group:beforeHIO,IPC with 5 min of ischemia and 5 min of reperfusionwas given;control group:no IPC was given.Liver functions,hepatic Caspase-3 activity,and apoptotic cells were comparedbetween these two groups.RESULTS:On postoperative days(POD)1,3 and 7,theaspartate transaminase(AST)and alanine transaminase(ALT)levels in the IPC group were significantly lower thanthose in the control group(P<0.05).On POD 3 and 7,thetotal bilirubin level in the IPC group was significantly lowerthan that in the control group(P<0.05).On POD 1,thealbumin level in the IPC group was higher than that in thecontrol group(P=0.053).After 1 h of reperfusion,bothhepatic Caspase-3 activity and apoptotic sinusoidal endothelialcells in the IPC group were significantly lower than thosein the control group(P<0.05).CONCLUSION:IPC has a potential protective effect onHCC patients with cirrhosis.Its protective mechanismunderlying the suppression of sinusoidal endothelial cellapoptosis is achieved by inhibiting Caspase-3 activity.     

Retrograde portal vein flow and transarterial chemoembolization in patients with hepatocellular carcinoma – a case–control study

Background and aims: Transarterial chemoembolization (TACE) is the most common treatment for hepatocellular carcinoma (HCC). In case of portal vein (PV) flow diversion, outcome may be compromised due to a decompensation of hepatic perfusion following arterial embolization. The aim of this study was to determine whether TACE in patients with retrograde PV flow results in a stronger deterioration of liver function and a poorer survival compared to patients with orthograde PV flow.

Methods: A database of 606 patients treated with TACE between 2000 and 2015 at Hannover Medical School was screened for Doppler ultrasound (US) findings on PV flow prior to TACE. A total of 407 patients were identified, among which 32 patients had retrograde PV flow.

Results: Patients with retrograde PV flow had significantly more often liver cirrhosis with advanced hepatic dysfunction (93.5% vs. 72.7%, p?p?>?.05). Patients with retrograde PV flow showed a trend for a shorter OS when matched for cirrhosis (12 vs. 21months, HR 1.51), Child-Pugh score/albumin-bilirubin grade (12 vs. 15 months). There was no difference in the deterioration of liver function after repeated treatments between both groups as assessed by increase of CP points and ALBI grade.

Conclusions: Retrograde PV flow alone was not a significant prognostic marker, but patients with retrograde PV flow and advanced liver cirrhosis treated with TACE had a very short survival. Assessment of PV flow prior TACE may be helpful in borderline cases considered for TACE.     

Should we give thromboprophylaxis to patients with liver cirrhosis and coagulopathy?

Patients with liver cirrhosis are characterized by decreased synthesis of both pro- and anticoagulant factors, and recently there has been evidence of normal generation of thrombin resulting in a near normal haemostatic balance. Although it is generally recognized that bleeding is the most common clinical manifestation as a result of decreased platelet function and number, diminished clotting factors and excessive fibrinolysis, hypercoagulability may play an under recognized but important role in many aspects of chronic liver disease. In fact, they can encounter thrombotic complications such as portal vein thrombosis, occlusion of small intrahepatic vein branches and deep vein thrombosis (DVT). In particular, patients with cirrhosis appear to have a higher incidence of unprovoked DVT and pulmonary embolism (PE) compared with the general population. In dedicated studies, the incidence of DVT/PE ranges from 0.5% to 1.9%, similar to patients without comorbidities, but lower than patients with other chronic diseases (i.e, renal or heart disease). Surprisingly, standard coagulation laboratory parameters are not associated with a risk of developing DVT/PE; however, with multivariate analysis, serum albumin level was independently associated with the occurrence of thrombosis. Moreover, patients with chronic liver disease share the same risk factors as the general population for DVT/PE, and specifically, liver resection can unbalance the haemostatic equilibrium towards a hypercoagulable state. Current guidelines on antithrombotic prophylaxis do not specifically comment on the cirrhotic population as a result of the perceived risk of bleeding complications but the cirrhotic patient should not be considered as an auto-anticoagulated patient. Therefore, thromboprophylaxis should be recommended in patients with liver cirrhosis at least when exposed to high-risk conditions for thrombotic complications. Low molecular weight heparins (LWMHs) seem to be relatively safe in this group of patients; however, when important risk factors for bleeding are present, graduated compression stockings or intermittent pneumatic compression should be considered.     

Should we continue surveillance for hepatocellular carcinoma and gastroesophageal varices in patients with cirrhosis and cured HCV infection?

Hepatocellular carcinoma (HCC) and variceal bleeding are among the most common causes of liver-related mortality in patients with hepatitis C virus (HCV)-induced cirrhosis. Current guidelines recommend HCC and gastroesophageal varices (GEV) surveillance in patients with HCV infection and cirrhosis. However, since the recent introduction of direct-acting antivirals, most patients with cirrhosis are now cured of their chronic HCV infection. As virological cure is considered to substantially reduce the risk of cirrhosis-related complications, this review discusses the current literature concerning the surveillance of HCC and GEV in patients with HCV-induced cirrhosis with a focus on the setting following sustained virological response.     

Should surveillance for liver cancer be modified in hepatitis C patients after treatment‐related cirrhosis regression?

Surveillance of hepatocellular carcinoma (HCC) with abdominal ultrasound (US) is recommended for patients with advanced liver fibrosis because of hepatitis C virus (HCV) infections who achieve a sustained virological response (SVR) to antiviral therapy. HCC, in fact, may still develop following SVR as a consequence of long‐standing carcinogenic activity of either HCV or hepatic fibrosis, whereas HCC risk in non‐viraemic patients may also be driven by cofactors like alcohol abuse or diabetes. This explains the debate on whether surveillance for HCC should be continued in patients with documented cirrhosis regression following a SVR too. While regression of cirrhosis was documented to occur in a majority of patients with compensated cirrhosis 5 years after an SVR to interferon, it should be noted that this clinical benefit could be the consequence of treating a selected population with well‐compensated liver disease who in fact were interferon able. This may not be the case for most real‐life patients with advanced cirrhosis receiving direct antivirals, in whom liver fibrosis may have reached a point of no‐return thus potentially preventing the recovery of a normal liver architecture following SVR. Both invasive and non‐invasive tools have suboptimal diagnostic accuracy for fibrosis regression in non‐viraemic patients, and this prompts to follow international societies’ recommendation to perform surveillance in patients with advanced liver fibrosis achieving a SVR, independently on liver histology outcome.     

α-Fetoprotein,tissue polypeptide antigen and ferritin in diagnosing primary hepatocellular carcinoma in patients with liver cirrhosis

Summary This study was undertaken in order to compare the usefulness of three indices of tumour proliferation in detecting primary hepatocellular carcinoma (HCC) and in differentiating this neoplasm from liver cirrhosis. In 10 patients with HCC and in 63 with liver cirrhosis serum -fetoprotein (AFP), tissue polypeptide antigen (TPA) and ferritin were assayed. Increased levels of AFP but not of TPA and ferritin were observed in HCC as compared to liver cirrhosis. The receiver-operating characteristic curves demonstrated that AFP is more discriminating between HCC and liver cirrhosis than the other two markers. Correlations between liver function tests and serum markers were observed in liver cirrhosis but not in HCC. We can conclude that AFP is more useful than TPA and ferritin in detecting HCC in patients with liver cirrhosis, owing to the high frequency of false positive results of the latter two indices in liver cirrhosis. Liver dysfunction is probably involved in increasing all these markers of malignancy, thus reducing the specificity of these tests.Abbreviations AFP -tetoprotein - TPA tissue polypeptide antigen - HCC primary hepatocellular carcinoma Partially supported by a grant of the Italian National Research Council, Special Project Oncology, contract 87.01.541.04. Under the auspices of the R. Farini association for gastroenterological research     

Interferon plus ribavirin and interferon alone in preventing hepatocellular carcinoma： A prospective study on patients with HCV related cirrhosis

AIM: To determine the role of interferon (IFN) with or without ribavirin in preventing or delaying hepatocellular carcinoma (HCC) development in patients with hepatitis C virus (HCV) related cirrhosis. Data on the preventive effect of IFN plus ribavirin treatment are lacking. METHODS: A total of 101 patients (62 males and 39 females, mean age 55.1+/-1.4 years) with histologically proven HCV related liver cirrhosis plus compatible biochemistry and ultrasonography were enrolled in the study. Biochemistry and ultrasonography were performed every 6 mo. Ultrasound guided liver biopsy was performed on all detected focal lesions. Follow-up lasted for 5 years. Cellular proliferation, evaluated by measuring Ag-NOR proteins in hepatocytes nuclei, was expressed as AgNOR-Proliferative index (AgNOR-PI) (cut-off = 2.5). Forty-one patients (27 males, 14 females) were only followed up after the end of an yearly treatment with IFN-alpha2b (old treatment control group = OTCG). Sixty naive patients were stratified according to sex and AgNOR-PI and then randomized in two groups: 30 were treated with IFN-alpha2b + ribavirin (treatment group = TG), the remaining were not treated (control group = CG). Nonresponders (NR) or relapsers in the TG received further IFN/ribavirin treatments after a 6 mo of withdrawal. RESULTS: AgNOR-PI was significantly lowered by IFN (P<0.001). HCC incidence was higher in patients with AgNOR-PI>2.5 (26% vs 3%, P<0.01). Two NR in the OTCG, none in the TG and 9 patients in the CG developed HCC during follow-up. The Kaplan-Mayer survival curves showed statistically significant differences both between OTCG and CG (P<0.004) and between TG and CG (P<0.003). CONCLUSION: IFN/ribavirin treatment associated with re-treatment courses of NR seems to produce the best results in terms of HCC prevention. AgNOR-PI is a useful marker of possible HCC development.     

Hepatic resection for hepatocellular carcinoma in patients with Child–Pugh's A cirrhosis: is clinical evidence of portal hypertension a contraindication?

Background

According to international guidelines [European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD)], portal hypertension (PHTN) is considered a contraindication for liver resection for hepatocellular carcinoma (HCC), and patients should be referred for other treatments. However, this statement remains controversial. The aim of this study was to elucidate surgical outcomes of minor hepatectomies in patients with PHTN (defined by the presence of esophageal varices or a platelet count of <100 000 in association with splenomegaly) and well-compensated liver disease.

Methods

Between 1997 and 2012, a total of 223 cirrhotic patients [stage A according to the Barcelona Clinic Liver Cancer (BCLC) classification] were eligible for this analysis and were divided into two groups according to the presence (n = 63) or absence (n = 160) of PHTN. The demographic data were comparable in the two patient groups.

Results

Operative mortality was not different (only one patient died in the PHTN group). However, patients with PHTN had higher liver-related morbidity (29% versus 14%; P = 0.009), without differences in hospital stay (8.8 versus 9.8 days, respectively). The PHTN group showed a worse survival rate only if biochemical signs of liver decompensation existed. Multivariate analysis identified albumin levels as an independent predictive factor for survival.

Conclusions

PHTN should not be considered an absolute contraindication to a hepatectomy in cirrhotic patients. Patients with PHTN have short- and long-term results similar to patients with normal portal pressure. A limited hepatic resection for early-stage tumours is an option for Child–Pugh class A5 patients with PHTN.     

Interferon plus ribavirin and interferon alone in preventing hepatocellular carcinoma: A prospective study on patients with HCV related cirrhosis

AIM:To determine the role of interferon(IFN)with or withoutribavirin in preventing or delaying hepatocellular carcinoma(HCC)development in patients with hepatitis C virus(HCV)related cirrhosis.Data on the preventive effect of IFN plusribavirin treatment are lacking.METHODS:A total of 101 patients(62 males and 39 females,mean age 55.1±1.4 years)with histologically proven HCVrelated liver cirrhosis plus compatible biochemistry andultrasonography were enrolled in the study.Biochemistryand ultrasonography were performed every 6 mo.Ultrasoundguided liver biopsy was performed on all detected focallesions.Follow-up lasted for 5 years.Cellular proliferation,evaluated by measuring Ag-NOR proteins in hepatocytesnuclei,was expressed as AgNOR-Proliferative index(AgNOR-PI)(cut-off=2.5).Forty-one patients(27 males,14 females)were only followed up after the end of anyearly treatment with IFN-alpha2b(old treatment controlgroup=OTCG).Sixty naive patients were stratified accordingto sex and AgNOR-PI and then randomized in two groups:30 were treated with IFN-alpha2b ribavirin(treatmentgroup=TG),the remaining were not treated(control group=CG).Nonresponders(NR)or relapsers in the TG receivedfurther IFN/ribavirin treatments after a 6 mo of withdrawal.RESULTS:AgNOR-PI was significantly lowered by IFN(P<0.001).HCC incidence was higher in patients withAgNOR-PI>2.5(26% vs3%,P<0.01).Two NR in the OTCG,none in the TG and 9 patients in the CG developed HCCduring follow-up.The Kaplan-Mayer survival curves showedstatistically significant differences both between OTCG andCG(P<0.004)and between TG and CG(P<0.003).CONCLUSION:IFN/ribavirin treatment associated with re-treatment courses of NR seems to produce the best resultsin terms of HCC prevention.AgNOR-PI is a useful markerof possible HCC development.Azzaroli F,Accogli E,Nigro G,Trerè D,Giovanelli S,MiracoloA,Lodato F,Montagnani M,Tamé M,Colecchia A,Mwangemi C,Festi D,Roda E,Derenzini M,Mazzella G.Interferon plusribavirin and interferon alone in preventing hepatocellularcarcinoma:A prospective study on patients with HCV relatedcirrhosis.World J Gastroenterol 2004;10(21):3099-3102http://www.wjgnet.com/1007-9327/10/3099.asp     

Will the collaboration of surgery and external radiotherapy open new avenues for hepatocellular carcinoma with portal vein thrombosis?

Portal invasion of hepatocellular carcinoma(HCC)occurs in 12.5%-40%of patients diagnosed with cancer and yields poor clinical outcomes.Since it is a common cause of inoperability,sorafenib was regarded as the standard treatment for HCC in the Barcelona Clinic of Liver Cancer guidelines.However,the median survival of the Asian population was only approximately 6 mo,and the tumor response rate was less than moderate(<5%).Various locoregional modalities were performed,including external beam radiotherapy(EBRT),transarterial chemoembolization,hepatic arterial infusion chemotherapy,and surgery,alone or in combination.Among them,EBRT is a noninvasive method and can safely treat tumors involving the major vessels.Palliative EBRT has been commonly performed,especially in East Asian countries,where locally invasive HCC is highly prevalent.Although surgery is not commonly indicated,pioneering studies have demonstrated encouraging results in recent decades.Furthermore,the combination of neo-or adjuvant EBRT and surgery has been recently used and has significantly improved the outcomes of HCC patients,as reported in a few randomized studies.Regarding systemic modality,a combination of novel immunotherapy and vascular endothelial growth factor inhibitor showed results superior to that of sorafenib as a first-line agent.Future clinical trials investigating the combined use of these novel agents,surgery,and EBRT are expected to improve the prognosis of HCC with portal invasion.