Is the American Association for the Study of Liver Diseases recommendation for hepatocellular carcinoma screening a cul-de-sac?

The American Association for the Study of Liver Diseases just confirmed a grade Ⅰ recommendation for hepatocellular carcinoma (HCC) screening despite growing controversy. Why should HCC be an exception in the long list of other cancers where the feasibility and the efficacy of screening were investigated by randomized trials? Only 12.0% of United States patients are screened, a fact that precludes efficacy, and there are no relevant figures on the benefit-risk ratio. The ethics of belief is a treacherous reef. Screening is not just performing a test, but is a public health issue: a national program is needed to ensure minimal participation, quality controls and evaluation of the results to improve the process. There are also serious concerns regarding undisclosed potential conflicts of interest.     

Surveillance for early diagnosis of hepatocellular carcinoma: is it effective in intermediate/advanced cirrhosis?

OBJECTIVES: Surveillance of cirrhotic patients for early diagnosis of hepatocellular carcinoma (HCC), based on ultrasonography and alpha-fetoprotein (AFP) measurement, is widely used. Its effectiveness depends on liver function, which affects the feasibility of treatments and cirrhosis-related mortality. We assessed whether patients with intermediate/advanced cirrhosis benefit from surveillance. METHODS: We selected 468 Child-Pugh class B and 140 class C patients from the ITA.LI.CA database, including 1,834 HCC patients diagnosed from January 1987 to December 2004. HCC was detected in 252 patients during surveillance (semiannual 172, annual 80 patients; group 1) and in 356 patients outside surveillance (group 2). Survival of surveyed patients was corrected for the estimated lead time. RESULTS: Child-Pugh class B: cancer stage (P < 0.001) and treatment distribution (P < 0.001) were better in group 1 than in group 2. The median (95% CI) survivals were 17.1 (13.5-20.6) versus 12.0 (9.4-14.6) months and the survival rates at 1, 3, and 5 yr were 60.4%versus 49.2%, 26.1%versus 16.1%, and 10.7%versus 4.3%, respectively (P= 0.022). AFP, gross pathology, and treatment of HCC were independent prognostic factors. Child-Pugh class C: cancer stage (P= 0.001) and treatment distribution (P= 0.021) were better in group 1 than in group 2. Nonetheless, median survival did not differ: 7.1 (2.1-12.1) versus 6.0 (4.1-7.9) months (P= 0.740). CONCLUSIONS: These results suggest surveillance be offered to class B patients and maintained for class A patients who migrate to the subsequent class. Surveillance becomes pointless in class C patients probably because the poor liver function adversely affects the overall mortality and HCC treatments.     

Prophylaxis for venous thromboembolism after resection of hepatocellular carcinoma on cirrhosis: Is it necessary?

AIM: To assess the safety and effectiveness of prophylaxis for venous thromboembolism (VTE) in a large population of patients with hepatocellular carcinoma (HCC) on cirrhosis.METHODS: Two hundred and twenty nine consecutive cirrhotic patients with HCC who underwent hepatic resection were retrospectively evaluated to assess whether there was any difference in the incidence of thrombotic or hemorrhagic complications between those who received and those who did not receive prophylaxis with low-molecular weight...     

Expression of β-catenin in hepatocellular carcinoma

AIM: The p-catenin has been recognized as a critical member of the Wnt signaling pathway and plays an important role in the generation/differentiation of many tissues. Inappropriate activation of this pathway has been implicated in carcinogenesis. The mechanism underlying the development as well as its prognosis of hepatocellular carcinoma (HCC) has remained unclear. The purpose of this study is to analyze the expression of p-catenin in HCC in relation to histological grades and viral hepatitis backgrounds. METHODS: Thirty-two sections were selected at random from autopsy and surgical cases of HCC. Immuohistologically, the location and positivity of p-catenin expression in HCC was examined. RESULTS: Normal hepatocytes did not express p-catenin. In 78% of HCC p-catenin was expressed at the membrane of the cells, with or without cytoplasmic and/or nuclear expression. The tumor cells with well- and moderately-differentiated grades expressed frequently at the membrane and cytoplasm compared with poorly-differentiated type. Nuclear expression of p-catenin was prone to occur in the tumor cells of poorly-differentiated grade. There were 15% of hepatitis C virus (HCV) backgrounds with nuclear expression. In contrast, there was 38% with nuclear expression in hepatitis B virus (HBV) backgrounds. In nonB-nonC hepatitis, no case expressed nuclear p-catenin. CONCLUSION: The β-catenin expression in HCC cells was heterogenous among types of hepatitis viral infection. Wnt signaling pathway might be deeply involved in less-differentiated HCC and HBV background.     

Is inconsistency of α-fetoprotein level a good prognosticator for hepatocellular carcinoma recurrence?

AIM: To identify the clinical outcomes of hepato-cellular carcinoma (HCC) patients with inconsistent α-fetoprotein (AFP) levels which were initially high and then low at recurrence.METHODS: We retrospectively included 178 patients who underwent liver resection with high preoperative AFP levels (≥ 200 ng/dL). Sixty-nine HCC patients had recurrence during follow-up and were grouped by their AFP levels at recurrence: group Ⅰ, AFP ≤ 20 ng/dL (n = 16); group Ⅱ, AFP 20-200 ng/dL (n = 24); and group Ⅲ, AFP ≥ 200 n...     

Sorafenib and entecavir:The dioscuri of treatment for advanced hepatocellular carcinoma?

Hepatitis B virus(HBV) is responsible for 50%-80% of cases of hepatocellular carcinoma(HCC) worldwide.Entecavir(ET) is a potent inhibitor of chronic HBV-DNA polymerase,inhibiting both the priming and elongation steps of viral DNA replication.Sorafenib(SO) has proven efficacy in prolonging survival in patients with advanced HCC.In this frontier report we discuss a possible way to optimize treatment outcomes in patients with HBV and HCC by treatment with ET and SO,on the basis of our practice and published evidence from the literature.     

Psoriatic arthritis: How to diagnosis it early?

Psoriatic arthritis (PsA) is an inflammatory arthritis that usually develops after the onset of cutaneous psoriasis. There is evidence that early diagnosis will lead to better long-term outcomes. Identifying inflammatory arthritis in subjects with psoriasis is the key to early diagnosis of PsA. Screening strategies using questionnaires or biomarkers targeted at subjects with psoriasis may result in early identification of PsA. This article reviews the importance of early diagnosis of PsA and the strategies available for screening psoriasis patients for PsA.     

Surveillance for hepatocellular carcinoma in chronic viral hepatitis: Is it time to personalize it?

Surveillance with abdominal ultrasound with or without alpha-fetoprotein is recommended by clinical practice guidelines for patients who are considered to be at risk of developing hepatocellular carcinoma (HCC), including those with cirrhosis, advanced fibrosis and special subgroups of chronic hepatitis B (CHB). Application of the standard surveillance strategy to all patients with chronic liver disease (CLD) with or without cirrhosis imposes major sustainability and economic burdens on healthcare systems. Thus, a number of HCC risk scores were constructed, mainly from Asian cohorts, to stratify the HCC prediction in patients with CHB. Similarly, even if less than for CHB, a few scoring systems were developed for chronic hepatitis C patients or cirrhotic patients with CLD of different etiologies. Recently, a few newsworthy HCC-risk algorithms were developed for patients with cirrhosis using the combination of serologic HCC markers and clinical parameters. Overall, the HCC risk stratification appears at hand by several validated multiple score systems, but their optimal performance is obtained only in populations who show highly homogenous clinic-pathologic, epidemiologic, etiologic and therapeutic characteristics and this limitation poses a major drawback to their sustainable use in clinical practice. A better understanding of the dynamic process driving the progression from CLD to HCC derived from studies based on molecular approaches and genetics, epigenetics and liquid biopsy will enable the identification of new biomarkers to define the individual risk of HCC in the near future, with the possibility to achieve a real and cost/effective personalization of surveillance.     

Liver transplantation for hepatocellular carcinoma: Where do we stand?

Hepatocellular carcinoma represents an important cause of morbidity and mortality worldwide. It is the sixth most common cancer and the fourth leading cause of cancer death. Liver transplantation is a key tool for the treatment of this disease in human therefore hepatocellular carcinoma is increasing as primary indication for grafting. Although liver transplantation represents an outstanding therapy for hepatocellular carcinoma, due to organ shortage, the careful selection and management of patients who may have a major survival benefit after grafting remains a fundamental question. In fact, only some stages of the disease seem amenable of this therapeutic option, stimulating the debate on the appropriate criteria to select candidates. In this review we focused on current criteria to select patients with hepatocellular carcinoma for liver transplantation as well as on the strategies (bridging) to avoid disease progression and exclusion from grafting during the stay on wait list. The treatments used to bring patients within acceptable criteria (down-staging), when their tumor burden exceeds the standard criteria for transplant, are also reported. Finally, we examined tumor reappearance following liver transplantation. This occurrence is estimated to be approximately 8%-20% in different studies. The possible approaches to prevent this outcome after transplant are reported with the corresponding results.     

Re-evaluation of antitumor effects of combination chemotherapy with interferon-α and 5-fluorouracil for advanced hepatocellular carcinoma

AIM: To evaluate the efficacy of combination chemotherapy with interferon-α(IFNα) and 5-fluorouracil(5-FU) in patients with advanced hepatocellular carcinoma (HCC). METHODS: Twenty-eight HCC patients in advanced stage were enrolled in the study. They were treated with IFNa/ 5-FU combination chemotherapy. One cycle of therapy lasted for 4 wk. IFNα(3×10~6 units) was subcutaneously injected thrice weekly on days 1, 3, and 5 for 3 wk, and 5-FU (500 mg/d) was administered via the proper hepatic artery for 5 consecutive days per week for 3 wk. No drugs were administered during the 4~(th) wk. The effect of combination chemotherapy was evaluated in each patient after every cycle based on the reduction of tumor volume. RESULTS: After the 1~(st) cycle of therapy, 16 patients showed a partial response (PR, 57.1%) but none showed a complete response (CR, 0%). At the end of therapy, the number of patients who showed a CR, PR, or no response (NR) was 1, 10, and 17, respectively. The response rate for therapy (CR+PR) was 21.5%. Biochemical tests before therapy were compared between responsive (CR+PR) and non-responsive (NR) patients, but no significant differences were found for any of the parameters examined, indicating that no reasonable predictors could be identified in our analysis. CONCLUSION: Attempts should be made to discriminate between responders and non-responders by evaluating tumor size after the first cycle of IFNα/5-FU combination chemotherapy. For non-responders, therapy should not proceed to the next cycle, and instead, different combination of anticancer drugs should be explored.     

Usefulness of serum des-γ-carboxy prothrombin in detection of hepatocellular carcinoma

AIM: To evaluate whether DCP is better than AFP for differentiating HCC from nonmalignant liver disease and further evaluate the usefulness of DCP in early diagnosis of small HCC. METHODS: Serum DCP and AFP levels were determined in 127 patients. Among these patients, 32 were with non-cirrhotic chronic hepatitis, 34 were with compensated cirrhosis, and 61 were with HCC. The cut-off value for the DCP and AFP were set as 40 mAU/mL and 20 ng/mL, respectively. To compare the diagnostic value of DCP and AFP in distinguishing HCC from nonmalignant chronic liver disease, receiver operating characteristic (ROC) curves were constructed for each assay. RESULTS: The accuracy, sensitivity, and specificity of DCP were higher than AFP in detecting HCC (81.9%, 77%, and 86.4% re 68.5%, 59%, and 77.3%, respectively). The area under the ROC (AUROC) curves revealed that DCP had a better accuracy than AFP in diagnosis of HCC (0.85 [95%CI, 0.78-0.91] vs 0.73 [95%CI, 0.65-0.81], P= 0.013). In 39 patients with solitary HCC, the positive rates of DCP were 100% in patients with tumor size larger than 3 cm, 66.7% in patients with tumor size 2-3 cm and 50% in patients with tumor size less than 2 cm. The positive rates of AFP in patients with tumor size larger than 3 cm, 2-3 cm and less than 2 cm were 55.6%, 50%, and 33.3%, respectively. The median level of DCP in HCC patients with tumor size larger than 3 cm was significantly higher than those with tumor size 2-3 cm and those with the size of less than 2 cm. CONCLUSION: Our study indicates that DCP has a better diagnostic value than AFP in differentiating HCC from nonmalignant chronic liver disease. DCP has not only a stronger correlation with HCC than AFP in tumor size but also more effectiveness than AFP in detecting small size of HCC.     

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.     

Intermediate hepatocellular carcinoma: How to choose the best treatment modality?

Intermediate stage, or stage B according to Barcelona Clinic Liver Cancer classification, of hepatocellular carcinoma (HCC) comprises a heterogeneous population with different tumor burden and liver function. This heterogeneity is confirmed by the large variability of treatment choice and disease-relate survival. The aim of this review was to highlight the existing evidences regarding this specific topic. In a multidisciplinary evaluation, patients with large (> 5 cm) solitary HCC should be firstly considered for liver resection (LR). When LR is unfeasible, locoregional treatments are evaluable therapeutic options, being transarterial chemoembolization (TACE), the most used procedure. Percutaneous ablation can be an evaluable treatment for large HCC. However, the efficacy of all ablative procedures decrease as tumor size increases over 3 cm. In clinical practice, a combination treatment strategy [TACE or transarterial radioembolization (TARE)-plus percutaneous ablation] is “a priori” preferred in a relevant percentage of these patients. On the other hands, sorafenib is the treatment of choice in patients who are unsuitable to surgery and/or with a contraindication to locoregional treatments. In multifocal HCC, TACE is the first-line treatment. The role of TARE is still undefined. Surgery may have also a role in the treatment of multifocal HCC in selected cases (patients with up to three nodules, multifocal HCC involving 2-3 adjacent liver segments). In some patients with bilobar disease the combination of LR and ablative treatment may be a valuable option. The choice of the best treatment in the patient with intermediate stage HCC should be “patient-tailored” and made by a multidisciplinary team.     

“Metroticket” predictor for assessing liver transplantation to treat hepatocellular carcinoma:A single-center analysis in mainland China

AIM:To validate theMetroticketpredictor using a large cohort of liver transplantation(LT)patients with hepatocellular carcinoma(HCC)in China.METHODS:In total,230 cases of LT for HCC treatment at our center,from July 2000 to August 2008,were included in the present study.The predicted 1-,3-and 5-year post-LT survival rates were calculated using the Metroticket model(http://89.96.76.14/metroticket/calculator/).The predicted and observed long-term survival rates were then compared and analyzed.RESULTS:The predicted survival rates for all 230cases,as calculated by the Metroticket model,were64.7%and 56.2%at 3 and 5 years,respectively,and the observed survival rates for these patients were71.3%and 57.8%,respectively.For the 23 cases with macrovascular invasion,the predicted 5-year survival rate was 43.5%,whereas the observed 5-year survival rate was only 8.7%.For the 42 cases with microvascular invasion but an absence of macrovascular invasion,the predicted 5-year survival rate was 44.9%,and the observed 5-year survival rate was 50%.For the remaining 165 patients without any vascular invasion,the predicted 5-year survival rate was 65.8%,and the observed 5-year survival rate was 66.7%.CONCLUSION:The Metroticket model can be used to accurately predict survival in HCC-related LT cases with an absence of macrovascular invasion.     

Surveillance of colonic polyps: Are we getting it right?

Colorectal cancer(CRC) is the third most commonly diagnosed cancer worldwide. The identification of colonic polyps can reduce CRC mortality through earlier diagnosis of cancers and the removal of polyps: the precursor lesion of CRC. Following the finding and removal of colonic polyps at an initial colonoscopy, some patients are at an increased risk of developing CRC in the future. This is the rationale for postpolypectomy surveillance colonoscopy. However, not all individuals found to have colonic adenomas have a risk of CRC higher than that of the general population. This review examines the literature on post-polypectomy surveillance including current international clinical guidelines. The potential benefits of surveillance procedures must be weighed against the burden of colonoscopy: resource use, the potential for patient discomfort, and the risk of complications. Therefore surveillance colonoscopy is best utilised in a selected group of individuals at a high risk of developing cancer. Further study is needed into the specific factors conferring higher risk as well as the efficacy of surveillance in mitigating this risk. Such evidence will better inform clinicians and patients of the relative benefits of colonoscopic surveillance for the individual. In addition, the decision to continue with surveillance must be informed by the changing profile of risks and benefits of further procedures with the patient’s advancing age.     

How is it best to treat early rheumatoid arthritis patients?

During the past decade, many important changes have occurred in the treatment of rheumatoid arthritis, perhaps the most important of which has been the realization that early diagnosis and early treatment are critical. This has challenged our health-care systems to make sure that patients with early arthritis have access to the appropriate physicians. Additionally, the last decade has also seen many new treatment options become available for patients with rheumatoid arthritis. These new options have included the use of old drugs more effectively; the use of combinations of two or more disease-modifying anti-rheumatic drugs; new evidence to support the use of steroids; the resurrection of tetracyclines; the introduction of leflunomide; and, finally, the tumour necrosis factor inhibitors etanercept and infliximab. The availability of all these new options is clearly excellent news for patients with RA and their physicians. It is hoped that we will, in the next few years, better understand how most effectively to utilize these treatment options for the optimal care of our patients.     

Successful treatment of advanced hepatocellular carcinoma by combined administration of 5-fluorouracil and pegylated interferon-a

We report a case of hepatocellular carcinoma (HCC) treated successfully by transarterial chemoembolization (TACE) followed by combination therapy of 5-fluorouracil (5-FU) and pegylated interferon-α (PEG-IFN-α). In the present case, the patient had massive and advanced HCC with a diameter of over 8 cm located in segment 7 (S7) of the liver. Furthermore, the tumor invaded into the major branch of the portal vein (Vp3). After TACE, combined administration of 5-FU and PEG-IFN-α was performed for 5 mo. HCC was totally eradicated and the serum levels of tumor markers were markedly decreased by the treatment. Although it has been reported that the combined use of conventional IFN-a and 5-FU showed striking effects on HCC in some cases, this case may suggest the more promising effect of PEG-IFN-α with a long-lasting effect, in the combined use with 5-FU for the treatment of massive advanced HCC.