The European approach to hepatocellular carcinoma

Patients with cirrhosis of viral, metabolic or autoimmune origin are at high risk of developing hepatocellular carcinoma. Prospective surveillance based on semi-annual ultrasound examination of the abdomen has allowed for detection of small tumors in many patients, but it is not clear whether liver-related mortality was decreased in parallel. Prognostication in patients with hepatocellular carcinoma requires integrated assessment of tumor size and number, liver function and performance status. The therapeutic approach is to a large extent non-evidence based and the best treatment choice depends on individual patients characteristics, taking into account the local technological and therapeutic resources and skills. Since surgical resection, liver transplantation and percutaneous ablation have achieved a high rate of complete response in properly selected patients, these procedures are considered curative treatments. Being curative treatments applicable only to patients with a small tumor, hepatocellular carcinoma surveillance aimed at early detection of the tumor is the most practical approach for improving treatment outcome.     

Immunological approach to hepatocellular carcinoma

Summary. A library of monoclonal antibodies (MoAbs) has been produced against a human hepatocellular carcinoma (HCC) cell line designated FOCUS in order to study the antigenic properties of transformed hepatocytes. Several monoclonal antibodies (MoAbs) were initially selected for study since they bound to antigens which were overexpressed in HCC tissues compared with the adjacent uninvolved normal liver counterpart; in addition, these MoAbs revealed low level antigen expression on other normal human tissues. Subsequently, HCC cell lines were metabolically labelled and the antigens further characterized by immunoprecipitation and Western blot analysis. If the MoAb recognized a primary linear epitope on a protein, cloning was performed using a ΛGT11 cDNA expression library prepared from the FOCUS HCC cell line. These studies characterized the HCC associated antigen(s) at the molecular level. This review illustrates the value of such an experimental approach to search for and identify HCC associated antigens and emphasizes the biological properties of novel proteins may be defined and characterized by these techniques. More important, our investigations have described unique proteins that may not only be important in the pathogenesis of HCC but also demonstrates how such antigen-antibody systems may be used to develop strategies for immuno-targetting and gene therapy of HCC.     

Updated treatment approach to hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and its incidence will further increase, to reach a plateau in 2015–2020. The natural history of the disease is quite well known, except for its early stages, because the majority of patients at this stage are treated with radical approaches. Staging systems are key to predict the prognostics of patients with cancer, to stratify the patients according to prognostic variables in the setting of clinical trials, and to guide the therapeutic approach. The current knowledge of the disease, however, is not sufficient for recommending a staging system to be used worldwide. The conventional staging systems—Okuda stage, and TNM stage—have shown important limitations for classifying patients. Several new systems have been recently proposed, but only three of them have been validated. The Barcelona Clinic Liver Cancer (BCLC) staging classification links the stage of the disease to a specific treatment strategy. The Japan Integrated Staging (JIS) score has been proposed and used in Japan, although it needs Western validation. The Cancer of the Liver Italian Program (CLIP) score is mainly proposed for patients with advanced tumors. Early detection of HCC through surveillance programs allows the application of potentially curative therapies, such as resection, liver transplantation, and percutaneous ablation in patients with early tumors. The applicability of these treatments varies according to geographical distribution: from 50% to 70% of cases in Japan; 25% to 40% of cases in Europe and the United States; and fewer than 10% in Africa. There are no randomized controlled trials (RCTs) comparing any of the three major therapies. These studies are not feasible in the West. Therefore, there is no firm evidence to establish the optimal first-line treatment for small single HCC in patients with well-preserved liver function. Resection and transplantation achieve the best outcomes in well-selected candidates (5-year survival of 60%–70%), and compete as the first option from an intention-to-treat perspective. If surgery is precluded, local, nonsurgical therapies are applied. Percutaneous treatments provide good results (5-year survival of 40%–50%), but are unable to achieve response rates and outcomes comparable to those for surgical treatments, even when applied as the first option. Radiofrequency thermal ablation provides slightly better objective response rates than ethanol injection, but no survival advantages have been fully demonstrated. The remaining treatments have been assessed in the setting of around 70 RCTs conducted during the past 25 years. Chemoembolization has been shown to provide modest survival advantages in two RCTs and a metaanalysis, and is currently the mainstay of treatment in 10% of the whole HCC population. The ideal candidates for this option are patients with well-preserved liver function (Child-Pugh class A) and multinodular asymptomatic tumors without vascular invasion. Further RCTs are needed to assess the best chemotherapeutic agent and the ideal re-treatment schedule. There is no firstline option for patients with advanced HCC (vascular invasion, extrahepatic spread, or cancer-related symptoms). Systemic doxorubicin provides partial responses in 10% of cases, without proven survival advantages, and well-known treatment-related complications. Several other treatments, such as immunotherapy, internal radiation, tamoxifen, or anti-androgen agents, have not shown any relevant anti-tumoral effect or survival benefit. New drugs, such as tyrosine kinase inhibitors and anti-angiogenic agents, are currently being tested in the setting of clinical trials.     

肝细胞癌诊断标志物的研究进展

肿瘤标志物,又称为生物标志物,主要由肿瘤或宿主产生,能在体液或组织中检测到并有助于诊断和鉴别肿瘤。通过测定其存在或含量可辅助肿瘤的早期诊断、分子分型、分析病程、指导治疗、监测复发或转移及判断预后等。理想的标志物一般应敏感性高,能早期测出所有肿瘤患者,同时可用于以下一种或多种情况：早期诊断;筛检高危人群;监测病程进展与疗效、早期复发和转移或指导化学治疗的终点时间。     

Remodeling the surgical approach to hepatocellular carcinoma

Surgery for hepatocellular carcinoma has improved during the last two decades, and the improvement is mainly attributable to various innovations in liver surgery, such as establishment of the precise criteria for surgical indications, development of ultrasound-guided hepatectomy, and additional use of portal vein embolization. Operative mortality has fallen below 2% in the 1990's, and the 5-year survival rate reached, according to the results of a nationwide survey, nearly 50%. More than 90% of the hepatectomies in the authors' institution are performed without whole blood transfusion, and mean hospital stay is approximately 23 days. Moreover, no-mortality hepatectomy has been achieved since 1993.     

Clinicopathological study of minimum-sized hepatocellular carcinoma: An approach to the definition of early hepatocellular carcinoma

Clinicopathologic examination of 33 nodules from 23 cases of minimum-sized hepatocellular carcinoma (HCC), less than 15 mm in diameter, was carried out by imaging and clinical follow up. On ultrasound (US), 16 hypoechoic nodules (48%) and 15 hyperechoic nodules (45%) on angiography 7 tumour stains (21%) and on computerized tomography (CT) 3 low density nodules (9%) were detected. Of 27 nodules on lipiodol CT (LpCT), 7 lipiodol-deposited nodules (26%) were detected. Of 16 nodules on CO₂US angiography (US-angiography), 7 hypervascular (44%), 5 hypovascular (31%) and 4 isovascular nodules (25%) were detected. Of 13 nodules on CT during arterial portography (CTAP), 7 perfusion defect nodules (54%) were detected. The nodules were graded according to the Edmondson & Steiner Classification. Three nodules were resected; grossly, two were not distinct and one was poorly demarcated. Histologically, they were highly differentiated with irregularly-thin trabecular-patterned HCC where portal triads were detected. Cancer cells invaded the non-cancerous liver cells by replacement, and the border between the cancerous and non-cancerous regions was unclear; the latter region manifested chronic hepatitis or liver cirrhosis without hyperplasia. Minimum-sized HCC is characteristically hypovascular in arterial and portal supply of blood, of multicentric origin and of a well-differentiated pattern. Because the three resected nodules did not damage the liver acinus structure, they were considered to be an early stage of HCC.     

Diagnostic and therapeutic approach to hepatocellular carcinoma in the USA

It is now apparent that hepatocellular carcinoma is occurring with increasing frequency in the USA. This mirrors a trend that occurred in Japan approximately 10 years earlier. Although the approach to diagnosis and treatment are similar in Japan and the USA, there are some differences. Thus, imaging is the primary modality of diagnosis and computed tomography and magnetic resonance imaging are favored over ultrasound. Liver transplantation is an important modality oftherapy, which is associated with excellent survival and, with the introduction of the Model for End-Stage Liver Disease (MELD) system, there has been a sharp rise in liver transplants performed for hepatocellular carcinoma since 2002.     

An unusual approach to the spontaneous rupture of hepatocellular carcinoma

Our aim is to describe an unusual approach to the spontaneous rupture of a large hepatocellular carcinoma (HCC). A 45-year-old man, Hepatitis C virus (+) (HCV+), complaining of abdominal pain. During the investigation, a tumor affecting liver segments V, VI, VII and VIII, with the presence of fluid within the peritoneal cavity, suggesting hemoperitoneum, was found. The patient was submitted to an exploratory laparotomy, revealing a large hepatic tumor mass with capsule rupture in segment V, biopsy verified the diagnosis of HCC. After one week, a superselective chemoembolization of the nutrient artery of the tumor was performed; one month later, the patient was submitted to an embolization of the right portal branch, aimed at causing hypertrophy of the left lateral portion of the liver. A right hepatectomy was performed, as well as a nodulectomy in segment II, without complications along the 40 days subsequent to the portal embolization. The patient is currently on his 53rd postoperative month and evidences no tumor recurrence to the moment. Although the spontaneous rupture of HCC is uncommon, it can be today treated by combining interventionist radiology procedures and conventional liver resections, offering the patient a better chance of survival.     

血清高尔基体蛋白73诊断原发性肝癌价值探讨

目的探讨高尔基体蛋白73（GP73）诊断肝癌的价值。方法在肝癌107例、肝硬化53例、肝衰竭患者40例和健康人34例,采用ELISA法检测血清GP73浓度,采用ROC曲线寻找GP73诊断肝癌的最佳截断点,并与AFP进行比较,以评价GP73诊断肝癌的价值。结果原发性肝癌、肝硬化和慢性肝衰竭患者血清GP73水平分别为123.5±22.4ng/ml、108.9±30.3ng/ml和130.3±45.6ng/ml,均显著高于健康对照人群（44.1±38.9ng/ml,P〈0.05）;原发性肝癌、肝硬化和慢性肝衰竭患者血清AFP水平分别为236.6±205.3ng/ml、5.3±5.56ng/ml和53.9±40.40 ng/ml;选择血清GP73最佳截断点为77.4ng/ml,其诊断原发性肝癌的灵敏度为89.6%,特异度为100%,AFP的最佳截断点为35.4ng/ml,其诊断原发性肝癌的灵敏度为64.2%,特异度为100%;原发性肝癌患者血清GP73水平在不同年龄、性别、Edmondson分级和结节数目多寡之间无显著性相差,而在不同肿瘤大小、TNM分期和是否合并肝硬化方面均有显著性差异（P＜0.05）。结论血清GP73诊断肝癌的灵敏度优于AFP,尤其在AFP阴性患者诊断中有一定的意义。     

术前超声造影和术中快速冰冻病理切片诊断VETC癌巢型肝细胞癌的价值及患者手术方式选择研究

目的探讨术前超声造影、术中快速冰冻病理切片诊断血管包绕肿瘤细胞巢(VETC)癌巢型肝细胞癌(HCC)的价值及最优手术方式的选择。方法收集2013-10~2018-10经术后常规病理确诊的164例HCC的临床资料。免疫组化CD34染色观察VETC癌巢型、非癌巢型HCC形态学特点。统计癌巢型与非癌巢型HCC发生癌旁转移的比例。随访VETC癌巢型与非癌巢型HCC患者术后2年的复发率。分析解剖性肝切除与非解剖性肝切除对VETC癌巢型HCC患者术后2年复发率的影响。分析术前超声造影检查、术中快速冰冻病理切片诊断VETC癌巢型HCC的价值。结果164例HCC中,VETC癌巢型HCC占40.24%(66/164),其癌旁转移发生率为30.30%(20/66),显著高于非癌巢型HCC的10.20%(10/98)(P<0.05)。VETC癌巢型HCC和非癌巢型HCC术后2年的复发率分别为53.33%和36.90%。在VETC癌巢型HCC患者中,解剖性肝切除可显著降低HCC患者术后2年的复发率(P<0.05)。术前超声造影诊断VETC癌巢型HCC的灵敏度为81.82%,特异度为91.84%,准确率为87.80%,与术后常规病理检查结果具有较好的一致性(Kappa=0.744,P=0.000)。术中快速冰冻病理切片诊断VETC癌巢型HCC的灵敏度为93.94%,特异度为91.84%,准确率为92.68%,与术后常规病理检查结果具有较好的一致性(Kappa=0.849,P=0.000)。结论术前超声造影和术中冰冻病理切片可有效诊断VETC癌巢型HCC,解剖性肝切除是癌巢型HCC患者的优选术式。     

Human microbiome is a diagnostic biomarker in hepatocellular carcinoma

Background:Hepatocellular carcinoma(HCC)is the third leading cause of cancer mortality worldwide.Increasing evidence indicates a close relationship between HCC and the human microbiota.Herein,we reviewed the important potential of the human microbiota as a diagnostic biomarker of HCC.Data sources:Several innovative studies have investigated the characteristics of the gut and oral micro-biomes in patients with HCC and proposed that the human microbiome has the potential to be a diag-nostic biomarker of HCC.Literature from February 1999 to February 2019 was searched in the PubMed database using the keywordsmicrobiotaormicrobiomeormicrobeandliver cancerorhepato-cellular carcinoma,and the results of clinical and experimental studies were analyzed.Results:Specific changes occur in the human microbiome of patients with HCC.Moreover,the gut mi-crobiome and oral microbiome can be used as non-invasive diagnostic biomarkers for HCC.Furthermore,they also have certain diagnostic potential for precancerous diseases of HCC.The diagnostic potential of the blood microbiota and ascites microbiota in HCC will be gradually discovered in the future.Conclusions:The human microbiome is valuable to the diagnosis of HCC and provides a novel strategy for targeted therapy of HCC.The human microbiome may be widely used in the diagnosis,treatment and prognosis for multiple system diseases or cancers in the future.     

The diagnostic approach to deep venous thrombosis

Accurate diagnosis of deep vein thrombosis is important because untreated deep vein thrombosis can cause death or permanent impairment and because effective treatments are available. The approach to the diagnosis of deep vein thrombosis varies because of differences in local resources and expertise. Duplex ultrasonography with venous compression is the preferred initial test for the majority of outpatients who present with symptoms and signs that suggest acute deep vein thrombosis. Clinical outcome studies have shown the safety of withholding anticoagulants when two compression ultrasonography examinations are negative over a 5- to 7-day period. Alternative strategies, for example, combining clinical scores and D-dimer with compression ultrasonography, may also prove effective. In unusual circumstances, venography or even magnetic resonance imaging may be necessary.     

Laparoscopic hepatectomy: new approach for hepatocellular carcinoma

This article presents the rationale for the laparoscopic approach to liver surgery, showing the technique of fully endoscopic and endoscopic‐assisted formal and wedge hepatic resections. The early results are comparable to those of conventional surgery, with the benefits derived from minimal access surgery. Laparoscopic liver resections are technically feasible, with an acceptable morbidity and mortality rate, but extensive experience in conventional liver surgery, advanced laparoscopic surgery, and the availability of all requested technologies are indispensable prerequisites.     

Surgical approach for hepatitis C virus-related hepatocellular carcinoma

Hepatitis C is a strong prognostic factor for patients with hepatocellular carcinoma(HCC). Although liver resection and liver transplantation offer the chance of a cure for HCC,adequate management of co-existing infection with hepatitis C virus(HCV) is important to enable better long-term outcomes after surgery for HCV-related HCC. For patients undergoing liver resection,perioperative anti-viral treatment is recommended,since a decreased HCV viral load itself is reportedly associated with a lower tumor recurrence rate and a longer overall survival. For patients undergoing transplanatations for HCC complicated by end-stage liver disease,the post-transplant management of HCV infection is also necessary to prevent progressive graft injury caused by active hepatitis under the immunosuppressive condition that is needed after liver transplantation. Although only a few lines of solid evidence are available for postoperative antiviral treatment because of the limited indication and frequent adverse events caused by conventional high-dose combination interferon therapy,new direct acting anti-viral agents would enable interferon-free anti-viral treatment with a higher virologic response and minimal side effects.     

Combined approach for spontaneous rupture of hepatocellular carcinoma

Ruptured hepatocellular carcinoma is a rare, emergency occurrence in western countries with high mortality risk. A number of hypotheses have been formulated in order to explain the precise mechanism that leads to hepatocellular carcinoma (HCC) rupture: sub-capsular location, dimensions, portal hypertension, tumour necrosis, local increase of venous pressure due to the outflow reduction caused by neoplastic invasion, and the presence of a previous vascular injury which might predispose to HCC rupture. There is still a debate in the literature concerning the best approach in cases of HCC rupture. Surgery is the first option for treatment of acute abdominal bleeding. However the advent of endovascular treatments widens the range of possible therapies for acute bleeding control and subsequent ablation purposes. We report a case of hemoperitoneum from spontaneous rupture of undiagnosed HCC, that was treated successfully by emergency surgical resection followed by transarterial chemo-embolization for local recurrence.     

Serum chromogranin-A in hepatocellular carcinoma： Diagnostic utility and limits

AIM: The utility of serum alpha-fetoprotein (α-FP) for the detection of hepatocellular carcinoma (HCC) is questionable. High serum levels of chromogranin-A (CgA) have recently been reported in HCC. Impaired hepatic, renal, and heart functions influence circulating CgA. The aim of this study was to assess sensitivity and specificity of serum CgA as a marker of HCC in patients with liver cirrhosis (LC). METHODS: Serum CgA levels were measured by RIA in 339 patients of which 54 HCC, 132 LC, 45 chronic hepatitis (CH), 27 chronic heart failure (CHF), 36 chronic renal failure (CRF), 45 chronic inflammatory bowel disease (IBD) as disease controls and in 75 healthy controls. Patients with liver disease or IBD and concomitant renal and/or heart failure were excluded. Pearson correlation, non-parametric combination test and confidence interval analysis were used for statistical analysis. RESULTS: Serum CgA above normal values (100 ng/mL) were found in 83% of HCC patients, in 48% of LC patients, in 20% of CH patients, in 33% of IBD patients, in 92% of CRF patients, in 100% of CHF patients, and in none of the healthy controls. The mean CgA values in HCC (769±1046), in LC (249±369), in CH (87±94), in CRF (1390±1401), in CHF (577±539), in IBD (146±287) were significantly higher than those in healthy controls (48±18). HCC patients had higher CgA values (P<0.01) than LC, CH, and IBD patients but did not differ from those with CRF or CHF. The 95% CI for the mean (250-1289 ng/mL) in HCC patients was selected as a CgA range and the lower value of such range was assumed as cut-off. Sensitivity and specificity of CgA, calculated in relation to the cut-off in patients with cirrhosis and HCC, were respectively 61% (CI 48-73%) and 82% (CI 75-88%). Serum a-FP values were >200 ng/mL in 21% of the HCC patients and in none of the LC patients. No significant correlation was found between a-FP and CgA in patients with HCC and in patients with cirrhosis. CONCLUSION: When HCC is suspected and a-FP is normal or <200 ng/mL, CgA serum values represent a complementary diagnostic tool, unless kidney or heart failure is present.     

Multimodal therapy for hepatocellular carcinoma: A complementary approach to liver transplantation

Objective. To evaluate the survival benefit of multimodal therapy for the treatment of HCC.Background. Orthotopic liver transplantation (OLT) is considered the treatment of choice for selected patients with hepatocellular carcinoma (HCC). However, donor organ shortages and patients whose HCCs exceed OLT criteria require consideration of alternate therapeutic options such as hepatic resection, radiofrequency ablation (RFA), ethanol injection (EI), transarterial chemoembolization (TACE), and chemotherapy (CTX). This study was performed to evaluate the survival benefit of multimodal therapy for treatment of HCC as complementary therapy to OLT.Methods. A retrospective review was conducted of HCC patients undergoing therapy following multidisciplinary review at our institution from 1996 - 2006 with a minimum of a 2 year patient follow-up. Data were available on 247/252 patients evaluated. Relevant factors at time of diagnosis included symptoms, hepatitis B (HBV) and C (HCV) status, antiviral therapy, Child-Pugh classification, portal vein patency, and TNM staging. Patients underwent primary treatment by hepatic resection, RFA, EI, TACE, CTX, or were observed (best medical management). Patients with persistent or recurrent disease following initial therapy were assessed for salvage therapy. Survival curves and pairwise multiple comparisons were calculated using standard statistical methods.Results. Mean overall survival was 76.8 months. Pairwise comparisons revealed significant mean survival benefits with hepatic resection (93.2 months), RFA (66.2 months), and EI (81.1 months), compared with TACE (47.4 months), CTX (24.9 months), or observation (31.4 months). Shorter survival was associated with symptoms, portal vein thrombus, or Child-Pugh class B or C. HCV infection was associated with significantly shorter survival compared with HBV infection. Antiviral therapy was associated with significantly improved survival in chronic HBV and HCV patients only with earlier stage disease.Conclusion. Multimodal therapy is effective therapy for HCC and may be used as complementary treatment to OLT.