Sulfatase 2 Along with Syndecan 1 and Glypican 3 Serum Levels are Associated with a Prognostic Value in Patients with Alcoholic Cirrhosis-Related Advanced Hepatocellular Carcinoma
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Abstract
Purpose
Sulfatase 2 (SULF2) is an enzyme related to heparan sulfate modifications. Its expression,
as for some heparan sulfate proteoglycans expression, has been linked to hepatocellular
carcinoma (HCC) at mRNA level and immunohistochemistry staining on biopsy samples.
This study aims to evaluate the prognostic value of serum levels of SULF2 in patients
with alcoholic cirrhosis with or without HCC.
Patients and Methods
Two hundred and eighty-seven patients with alcoholic cirrhosis were enrolled in this
study: 164 without HCC, 57 with early HCC, and 66 with advanced HCC at inclusion.
We analyzed the association between SULF2 serum levels and prognosis using Kaplan–Meier
method and univariate and multivariate analysis using a Cox model.
Results
Child-Pugh C Patients have higher serum levels of SULF2 than Child-Pugh A patients.
Serum levels of SULF2 were also higher in patients with advanced HCC compared with
the other groups. In patients with advanced HCC, high serum levels of SULF2 were associated
with less favorable overall survival. Combination of SULF2 with Glypican 3 (GPC3)
and Syndecan 1 (SDC1) serum levels enhanced the ability to discriminate worst prognostic
in advanced HCC.
Conclusion
SULF2 along with GPC3 and SDC1 serum levels have been shown to be associated with
a prognostic value in advanced HCC.
No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.) 2008 Massachusetts Medical Society
Since the publication of the American Association for the Study of Liver Diseases (AASLD) practice guidelines on the management of hepatocellular carcinoma (HCC) in 2005, new information has emerged that requires that the guidelines be updated. The full version of the new guidelines is available on the AASLD Web site at http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf. Here, we briefly describe only new or changed recommendations. Surveillance and Diagnosis In the previous guideline, groups were specified for which surveillance was likely to be cost-effective because the hepatocellular carcinoma (HCC) incidence was high enough. New data on defining HCC risk have emerged for hepatitis B virus,1,2 hepatitis C virus,3 and autoimmune hepatitis.4 Surveillance is deemed cost-effective if the expected HCC risk exceeds 1.5% per year in patients with hepatitis C and 0.2% per year in patients with hepatitis B. Analysis of recent studies show that alpha-fetoprotein determination lacks adequate sensitivity and specificity for effective surveillance (and for diagnosis).5,6 Thus, surveillance has to be based on ultrasound examination. The recommended screening interval is 6 months. Diagnosis of HCC should be based on imaging techniques and/or biopsy.The 2005 diagnostic algorithm has been validated and the diagnostic accuracy of a single dynamic technique showing intense arterial uptake followed by “washout” of contrast in the venous-delayed phases has been demonstrated.7-9 Contrast-enhanced US may offer false positive HCC diagnosis in patients with cholangiocarcinoma and thus, has been dropped from the diagnostic techniques. The diagnostic algorithm is shown in Fig. 1. The application of dynamic imaging criteria should be applied only to patients with cirrhosis of any etiology and to patients with chronic hepatitis B who may not have fully developed cirrhosis or have regressed cirrhosis. Interpretation of biopsies and distinction between high-grade dysplatic nodules and HCC is challenging. Expert pathology diagnosis is reinforced by staining for glypican 3, heat shock protein 70, and glutamine synthetase, because positivity for two of these three stains confirms HCC.10 Fig. 1 Diagnostic algorithm for suspected HCC. CT, computed tomography; MDCT, multidetector CT; MRI, magnetic resonance imaging; US, ultrasound. Staging and Treatment of HCC The BCLC staging system (Fig. 2)11 has come to be widely accepted in clinical practice and is also being used for many clinical trials of new drugs to treat HCC. Therefore, it has become the de facto staging system that is used. Fig. 2 The BCLC staging system for HCC. M, metastasis classification; N, node classification; PS, performance status; RFA, radiofrequency ablation; TACE, transarterial chemoembolization. The recommendations for liver transplantation have not changed. No new data have emerged that can be used to define a new limit for expanding the patient selection criteria. The usefulness of portal pressure measurement to predict the outcome of patients and define optimal candidates for resection has been validated in Japan.12 Thus, resection should remain the first option for patients who have the optimal profile, as defined by the BCLC staging system. Although resection can be performed in some of these patients with advanced liver disease, the mortality is higher and they might be better served by liver transplantation or ablation. A cohort study of radiofrequency ablation demonstrated that complete ablation of lesions smaller than 2 cm is possible in more than 90% of cases, with a local recurrence rate of less than 1%.13 These data should be confirmed by other groups before positioning ablation as the first-line approach for very early HCC. The recommendations regarding patient selection and method of administration of chemoembolization are unchanged. Radioembolization, i.e., the intra-arterial injection of yttrium-90 bound to glass beads or to resin, has been shown to induce tumor necrosis, but there are no data comparing its efficacy to transarterial chemoembolization or to sorafenib treatment for those with portal vein invasion. However, for patients who have either failed transarterial chemoembolization or who present with more advanced HCC, new data indicates the efficacy of sorafenib (a multikinase inhibitor with activity against Raf-1, B-Raf, vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor, c-Kit receptors, among other kinases) in prolonging life.14,15 Sorafenib induces a clinically relevant improvement in time to progression and in survival The magnitude of the improvement in survival compares with other established molecular targeted therapies for other advanced cancers, and the associated toxicity is easily managed without treatment-related mortality. The most frequent adverse events were diarrhea (sorafenib versus placebo: 11% versus 2%) and hand–foot skin reaction (sorafenib versus placebo: 8% versus <1%), fatigue, and weight loss. Sorafenib is now considered first-line treatment in patients with HCC who can no longer be treated with potentially more effective therapies. In summary, in the past decade HCC has gone from being an almost universal death sentence to a cancer that can be prevented, detected at an early stage, and effectively treated. Physicians caring for patients at risk need to provide high-quality screening, proper management of screen-detected lesions, and provision of therapy that is most appropriate for the stage of disease.
[1
]Université Sorbonne Paris Nord, Laboratory for VascularTranslational Science, LVTS,
INSERM, UMR 1148 , Bobigny, F- 93000, France
[2
]Service de biochimie, Hôpital Avicenne, hôpitaux universitaires Paris-Seine-Saint-Denis,
Assistance publique Hôpitaux de Paris , Bobigny, F-93000, France
[3
]Service d’hépatologie, Hôpital Avicenne, AP-HP, hôpitaux universitaires Paris-Seine-Saint-Denis,
Assistance publique Hôpitaux de Paris , Bondy, F-93143, France
[4
]Service de radiologie, Hôpital Avicenne, hôpitaux universitaires Paris-Seine-Saint-Denis,
Assistance publique Hôpitaux de Paris , Bobigny, F-93000, France
[5
]Inserm, UMR 1162, Génomique fonctionnelle des tumeUrs solides , Paris, F-75010, France
[6
]Centre de Ressources Biologiques BB-0033-00027, Hôpital Avicenne, hôpitaux universitaires
Paris-Seine-Saint-Denis, Assistance publique Hôpitaux de Paris , Bobigny, F-93000, France
[7
]Service d’anatomie et cytologie pathologique, Hôpital Avicenne, hôpitaux universitaires
Paris-Seine-Saint-Denis, Assistance publique Hôpitaux de Paris , Bobigny, F-93000, France
Author notes
Correspondence: Erwan Guyot, Hôpitaux Universitaires Paris Seine-Saint-Denis, Laboratoire
Biochimie-Pharmacologie et Biologie Moléculaire , 125 Rue de Stalingrad, Bobigny,
93000, France, Tel +33 1 48 95 56 29, Fax +33 1 48 95 56 27, Email erwan.guyot@aphp.fr
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History
Date
received
: 21
July
2022
Date
accepted
: 07
October
2022
Page count
Figures: 6,
Tables: 3,
References: 55,
Pages: 15
Funding
Funded by:
Fondation Recherche en Alcoologie;
Funded by:
Société Nationale Française de Gastro-Entérologie;
This research was funded by grants from the Fondation Recherche en Alcoologie (FRA)
and Société Nationale Française de Gastro-Entérologie (SNFGE).
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