肝癌分子分型和转移复发的早期预测

肝细胞癌(hepatocellular carcinoma,HCC;简称肝癌)位居全球恶性肿瘤发病率第5位、死因第3位,在我国则已经成为恶性肿瘤的第2位杀手,肝癌的总5年生存率不足5%,每年新发病564000例,死亡549000例[1]。其预后如此之差的主要原因是肝癌容易侵犯门静脉而导致肝内播散,从而出现高肝内     

Comparison of Recurrence of Hepatocellular Carcinoma After Resection in Patients with Cirrhosis to Its Occurrence in a Surveilled Cirrhotic Population

The presence of cirrhosis is the only risk factor that is advocated for recurrence of hepatocellular carcinoma (HCC) 2 years after hepatic resection compared with noncirrhotic control subjects; however, data for cohorts of exclusively patients with cirrhosis are lacking. This study was designed to assess risk factors and annual incidence of early (<2 years) and late (>2 years) recurrence after resection of cirrhosis and to compare these findings with those of patients with cirrhosis enrolled in HCC surveillance programs (HCC occurrence). Data from 204 patients with cirrhosis resected for HCC and 150 surveilled for cirrhosis were retrospectively collected and compared using propensity score matching to overcome biases of nonrandomized study. Risk factors for early recurrence (incidence = 21.8%/year) were higher serum alpha-fetoprotein (AFP) levels, poorly differentiated tumor, and presence of microvascular invasion (P < 0.05). Risk factors for both late recurrence (18.4%/year) and HCC occurrence (3.3%/year) were male gender, older age, and higher serum transaminase levels; multiple primary tumors and higher AFP were additional risk factors for late recurrence and HCC occurrence respectively (P < 0.05). After propensity adjustment, resected patients with less than two risk factors for late recurrence showed an annual incidence of HCC (6.2%/year) similar to that of surveilled patients with ≥2 risk factors (5.8%/year; P = 0.898). Early and late recurrence of HCC for patients with cirrhosis after resection have distinct risk factors. Annual incidence of HCC 2 years or more after resection may be similar to that of general patients because the same risk factors are involved; assessment of these characteristics could be useful in tailoring clinical management.     

肝癌肝移植及肝癌肝切除术后复发特点的比较

目的 了解肝癌患者行肝移植或肝切除两种手术治疗后肿瘤复发的不同特点。方法 复习国内、外文献，比较二者的特点。结果 肝癌肝移植与肝癌肝切除术后复发率、复发时间、常见部位、复发相关因素、机理等方面均有所不同。结论 根据肝癌肝移植或肝切除术后复发的不同特点，针对性地加强肝癌复发的预防，重视复发后的治疗，以延长术后生存，改善生活质量。     

Correlation Between Postoperative Early Recurrence of Hepatocellular Carcinoma and Mesenchymal Circulating Tumor Cells in Peripheral Blood

Background

Circulating tumor cells (CTCs) have been actively studied for their functions in hepatocellular carcinoma (HCC) recurrence. However, the relationship between circulating tumor cells subtypes and hepatocellular carcinoma recurrence is still unclear.

Methods

CTCs were collected from the peripheral blood of 62 postoperative HCC patients. The CTCs were isolated with a filtration-based method. Multiplex fluorescence in situ hybridization was used to characterize the CTCs based on mRNA expression levels of epithelial and mesenchymal markers.

Results

Of the 62 HCC patients, 26 were diagnosed with early recurrence (ER) and 36 did not experience recurrence. Comparison between the recurrence group and the non-recurrence group showed the total number of CTCs, mesenchymal CTCs, and mixed CTCs in the recurrence group was significantly higher than in the non-recurrence group. Receiver operator characteristic (ROC) curve analysis was performed to define the positive cutoff values as follows: total number of CTCs ≥?4, mesenchymal CTCs ≥?1, and mixed CTCs ≥?3. Analysis showed that portal vein tumor thrombus (hazard ratio [HR] = 2.905, P = 0.023) and mesenchymal CTC positivity (HR = 3.453, P = 0.007) were independent risk factors for ER. The correlation between the presence of mesenchymal CTCs and time to recurrence was further examined, and the results showed significantly shortened postoperative disease-free survival in patients positive for mesenchymal CTCs (P < 0.001).

Conclusions

HCC patients with positive peripheral mesenchymal CTCs have a more serious risk of ER, which could be a potential biomarker in HCC prognosis monitoring.

     

Predictive Factors of Recurrence of Hepatocellular Carcinoma After Liver Transplantation: A Multivariate Analysis

We analyzed predictive risk factors for recurrence of hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT). We retrospectively analyzed the clinical data from 109 consecutive HCC patients who underwent OLT at our center from 1988 to 2007. We excluded all patients who died due to factors other than tumor recurrence within the first year (n = 24). The remaining 85 patients were enrolled in either a recurrence group (A; n = 19) or a nonrecurrence group (B; n = 66). Upon univariate analysis, the 2 groups were significantly different for 11 parameters. Group A included more females (P = .05), noncirrhotic liver recipients (P = .003), “up-to 7 status” patients (HCC with 7 as the sum of the size of the largest tumor [cm] and the number of tumors, P < .0001), patients exceeding Milan criteria (MC; P < .0001) or University of California San Francisco (UCSF) criteria (P < .0001), and OLT performed before 1999 (P = .003). Group A also showed a higher number of lesions (P = .035), a greater sum of diameters of the lesions (P < .0001), a major number of macrovascular (P < .0001) and microvascular invasions (P < .0001), and an increased number of G3-G4 grading (P = .006). Only microvascular invasion (P = .007) and exceeding UCSF criteria (P = .003) were independent risk factors for recurrence upon multivariate analysis. Patients with both these parameters are not candidates for OLT. Microvascular invasion is a good predictive parameter, but is impossible to detect preoperatively. New pre-OLT predictive risk factors are needed to achieve optimal results.     

肝脏超声造影在肝癌术后肝内复发转移早期诊断的应用价值

目的探讨肝脏超声造影在肝癌术后肝内复发转移早期诊断中应用价值。方法总结我院2008年3月至2012年5月68例原发性肝癌术后门诊和住院患者随访资料,超声造影(CEUS)检查68例,多层CT(MSCT)检查26例,磁共振(MRI)检查32例,数字减影血管造影(DSA)检查10例,肝穿刺病理检查6例。结果小于0.5 cm的复发或转移灶,肝脏CEUS检出率显著高于MSCT,同期检出率分别为85.7%、42.9%,差异具有统计学意义(P<0.05);MRI与CEUS同期检出率分别为72.2%、83.3%,差异具有统计学意义。直径在0.5 cm～1 cm复发或转移灶,MSCT与CEUS同期检出率分别为75%、93.4%,差异具有统计学意义(P<0.05)。大于1 cm的复发或转移灶,MSCT与CEUS同期检出率分别为80%、93.3%,差异具有统计学意义(P<0.05)。结论肝脏CEUS对于检出肝癌术后直径小于1 cm的复发或转移灶具有明显的优势,检出率高于MSCT和MRI,是肝癌术后随访早期诊断肝内复发转移的首选检查方法。     

Recurrence and Treatment Pattern in Long-Term Survivors with Hepatocellular Carcinoma: A Comparison between Radiofrequency Ablation and Surgery as a First-line Treatment

Background  

We compare the recurrence and treatment pattern in long-term survivors after radiofrequency ablation (RFA) and surgery for treatment of hepatocellular carcinoma (HCC).     

Recurrence Patterns and Prognostic Factors in Patients with Hepatocellular Carcinoma in Noncirrhotic Liver: A Multi-Institutional Analysis

Background

Hepatocellular carcinoma (HCC) primarily affects patients with a cirrhotic liver. Reports on the characteristics of patients with HCC in noncirrhotic liver, as well as predictors of recurrence and survival, are scarce.

Methods

Between 1992 and 2011, 334 patients treated for HCC in noncirrhotic liver were identified from three major hepatobiliary centers. Clinicopathological characteristics were analyzed and independent predictors of recurrence and overall survival were identified using Cox proportional hazards models.

Results

Median patient age was 58 years and 77 % were male. Most patients had a solitary (81 %) and poorly or undifferentiated tumor (56 %); median size was 6.5 cm. The majority of patients (96 %) underwent liver resection (microscopically negative margins in 94 %), whereas a few had transarterial chemoembolization or transplantation (4 %). Median recurrence-free survival (RFS) was 2.5 years, and 1- and 5-year RFS was 71.1, and 35 %, respectively. Elevated alkaline phosphatase levels [hazards ratio (HR) = 1.82], poor tumor differentiation (HR = 1.4), macrovascular invasion (HR = 2.18), and the presence of satellite lesions (HR = 1.9), or intrahepatic metastases (HR = 2.59) were independently associated with shorter RFS; in contrast, an intact tumor capsule independently prolonged RFS (HR = 0.46). Median overall survival was 5.9 years, and 1- and 5-year overall survival was 86.9, and 54.5 %, respectively. Tumor size ≥5 cm (HR = 2.27), macrovascular (HR = 2.72) or adjacent organ invasion (HR = 3.34), and satellite lesions (HR = 2.18) were independently associated with shorter overall survival, whereas an intact tumor capsule showed a protective effect (HR = 0.51).

Conclusions

Following resection of HCC in the setting of no cirrhosis, more than one-half of patients were alive after 5 years. However, even among patients with no cirrhosis, recurrence was common. Factors associated with RFS and overall survival included tumor characteristics, such as tumor capsule, satellite lesions, and vascular invasion.     

Role of Portal Vein Embolization in Hepatocellular Carcinoma Management and Its Effect on Recurrence: A Case-control Study

Background

Liver regeneration that occurs after portal vein embolization (PVE) may have adverse effects on the microscopic tumor foci in the residual liver mass in patients with hepatocellular carcinoma (HCC).

Methods

Fifty-four HCC patients with inadequate functional residual liver volume were offered PVE during a seven-year period. Among them, 34 (63%) patients underwent curative resection. They were compared with a matched control group (n?=?102) who underwent surgery without PVE. Postoperative complications, pattern of recurrence, and survival were compared between groups.

Results

In the PVE group, a pre-embolization functional residual liver volume of 23% (12–33.5%) improved to 34% (20–54%) (p?=?0.005) at the time of surgery. When the two groups were compared, minor (PVE, 24%; control, 29%; p?=?0.651) and major (PVE, 18%; control, 15%; p?=?0.784) complications were similar. After a follow-up period of 35?months (standard deviation 25?months), extrahepatic recurrences were detected in 10 PVE patients (29%) and 41 control patients (40%) (p?=?0.310). Intrahepatic recurrences were seen in 10 (29%) and 47 (46%) cases (p?=?0.109) in the PVE and control groups, respectively. In the PVE group, 41% (n?=?14) of the recurrences were detected before one year, compared with 42% (n?=?43) in the control group (p?=?1). Disease-free survival rates at 1, 3, and 5?years were 57, 29, and 26% in the control group and 60, 42, and 42% in the PVE group (log-rank, p?=?0.335). On multivariate analysis, PVE was not a factor affecting survival (p?=?0.821).

Conclusions

Portal vein embolization increases the resectability of initially unresectable HCC due to inadequate functional residual liver volume, and it has no deleterious oncological effect after major resection of HCC.     

Antiviral Therapy Decreases Recurrence of Hepatitis B Virus-related Hepatocellular Carcinoma after Curative Resection: A Meta-analysis

Background

The long-term outcome after curative resection of hepatocellular carcinoma (HCC) remains unsatisfactory because of the high incidence of recurrence. The present study was intended to assess the impact of hepatitis B virus (HBV) DNA level and nucleos(t)ide analog therapy on posthepatectomy recurrence of HBV-related HCC.

Methods

Eligible studies were identified through a computerized literature search. The pooled relative risk ratio (RR) with 95 % confidence interval (CI) was calculated using Review Manager 5.1 Software.

Results

Twenty studies with a total of 8,204 participants were included for this meta-analysis. Pooled analysis showed that high viral load was significantly associated with risk of recurrence (RR: 1.85, 95 % CI: 1.41–2.42; P < 0.001), poorer disease-free survival (DFS) (RR: 1.96, 95 % CI: 1.62–2.38; P < 0.001), and poorer overall survival (OS) (RR: 1.47, 95 % CI: 1.22–1.77; P < 0.001) of HBV-related HCC after surgical resection. Nucleos(t)ide analog therapy significantly decreased the recurrence risk (RR: 0.69, 95 % CI: 0.59–0.80; P < 0.001) and improved both DFS (RR: 0.70, 95 % CI: 0.58–0.83; P < 0.001) and OS (RR: 0.46, 95 % CI: 0.32–0.68; P < 0.001).

Conclusions

High DNA level is associated with posthepatectomy recurrence of HBV-related HCC. Nucleos(t)ide analog therapy improves the prognosis of HBV-related HCC after resection.     

A Prognostic Model and Treatment Strategy for Intrahepatic Recurrence of Hepatocellular Carcinoma after Curative Resection

Background  

The aim of this study was to evaluate the prognostic factors for intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resection.     

Transplantation in Hepatocellular Carcinoma: Observational Multivariate Analysis of Survival and Recurrence Factors in 414 Patients

BackgroundWe sought to identify the risk factors involved in survival of and tumor recurrence in patients with hepatocellular carcinoma (HCC) undergoing liver transplant (LTx).MethodsWe conducted a retrospective observational study and analyzed the medical records of 414 patients with HCC undergoing deceased donor LTx in São Paulo between January 2007 and December 2011. Multifactorial analysis of survival and recurrence was performed using clinical, laboratory, and pathology data.ResultsThe mortality rate was 27.5%; mean survival time was 68.1 months (95% confidence interval, 64.7-71.6); and estimated 1-, 3-, and 5-year survival probabilities were 83.8%, 75.8%, and 71.5%, respectively. Altered donor blood glucose, female sex, vascular invasion, advanced age, high Model for End‐Stage Liver Disease, and tumor size were the main risk factors determining survival in LTx recipients. Recurrence was noted in 7.2% of patients during the study period and was more frequent in women (hazard ratio, 2.6). Vascular invasion increased the chance of recurrence by 5.4 times. Each additional 1-year increase in recipient age increased the chance of recurrence by 5.6%, and each 1-mm increase in tumor size increased the chance of recurrence by 3%.ConclusionsRisk factors for reduced survival are donor blood glucose, female recipient, older age, increased Model for End‐Stage Liver Disease score, and nodule size. Tumor recurrence risk factors are vascular invasion, female sex, recipient age, and nodule size.     

Comparison of 3 Explant-Based Prognostic Models as Predictors of Hepatocellular Carcinoma Recurrence After Liver Transplantation: Analysis of Our Experience

Tumor load is often underdiagnosed on radiological examination previous to liver transplantation (LT) for hepatocarcinoma (CHC). Thus, post–liver transplant explant analysis is required following transplantation to assess the risk of the recurrence of CHC. The objectives were to compare the characteristics of CHC on pre-LT radiological examination and explant histology and validate three models for the prediction of recurrence based on data from a cohort of patients treated in our hospital.

HBV DNA and HBsAg Levels as Risk Predictors of Early and Late Recurrence after Curative Resection of HBV-related Hepatocellular Carcinoma

Background

Recent studies have shown that high hepatitis B virus (HBV) load is associated with increased risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). The aim of our study was to investigate the predictive role of HBV DNA and hepatitis B surface antigen (HBsAg) levels in early and late recurrence of HCC after curative resection in patients with HBV-related HCC.

Methods

From January 2008 to December 2010, a total of 248 patients underwent curative resection for HBV-related early-stage HCC (solitary tumor; < 5 cm in diameter or multinodular tumor; number of tumors ≤3 and diameter < 3 cm). We analyzed the predictive factors including HBV DNA and HBsAg levels for early recurrence (within 2 years) and late recurrence (after 2 years) of HCC after curative resection.

Results

The median follow-up duration was 33.3 months. Cumulative recurrence rates after resection at 1, 3, and 5 years were 16.6, 34.0, and 46.7 %, respectively. The multivariate analysis showed that risk factors for early recurrence were the presence of microvascular invasion (hazard ratio [HR] 3.86; p < 0.001), preoperative HBV DNA levels ≥ 20,000 IU/mL (HR 2.77; p < 0.001), and des-γ-carboxy prothrombin level ≥ 40 mAU/mL (HR 1.76; p = 0.045). Although, the risk factors for late recurrence by multivariate analysis were preoperative HBsAg levels ≥ 4,000 IU/mL (HR 2.80; p = 0.023) and age at resection ≥ 50 years (HR 3.22; p = 0.032).

Conclusion

The HBV DNA levels were associated with early recurrence, whereas HBsAg levels were associated with late recurrence after curative resection in HBV-related HCC.     

Prognostic Factors and Recurrence of Small Hepatocellular Carcinoma after Hepatic Resection or Microwave Ablation: A Retrospective Study

Purpose This study aims to analyze the long-term therapeutic results of small HCC less than 5 cm in diameter after microwave ablation (MA) or hepatic resection (HR) and choose factors that could predict metastasis and recurrence of small HCC. Materials and Methods The metastasis and recurrence of 194 patients with one HCC less than 5 cm in diameter who underwent curative HR or MA between January 1995 and December 2004 were reviewed retrospectively; immunohistochemistry was used to analyze the expressions of VEGF, bFGF, and c-Met in HCC tissues. Posttreatment prognostic factors were evaluated by multivariate analysis using Cox’s proportional hazards model. The variables included the expressions of these three proteins in HCC tissues, the clinical and pathologic characteristics of the patients. Results The retrospective study showed that 1-, 3-, and 5-year disease-free survival rates of patients with single HCC of diameter <5 cm were 71.3, 57.0 and 32.5%, respectively. Furthermore, 1-, 3-, and 5-year disease-free survival rates of the patients in MA group and resection group were 72.8, 54.0 and 33.0%; 68.5, 60.0, and 25.6%, respectively. There was no significant difference in disease-free survival rates between these two groups. The result of multivariate analysis showed that differentiation degree of HCC and the expressions of VEGF and c-Met in HCC tissues could be as the independent prognostic factors affecting metastasis and recurrence in patients with small HCC, whereas the methods of therapy had no impact on prognosis. Conclusions The metastasis and recurrence rate after MA is similar to that after HR, and the methods of therapy do not affect the prognosis of small HCC. The metastasis and recurrence of patients with small HCC will differ depending on tumor differentiation, expressions of VEGF and c-Met in HCC tissues.     

Adjuvant Therapy With Capecitabine Postpones Recurrence of Hepatocellular Carcinoma After Curative Resection: A Randomized Controlled Trial

Background  

Postoperative recurrence of hepatocellular carcinoma (HCC) is a major problem after surgical resection. To date, adjuvant chemotherapy or other adjuvant modalities have not been proven effective in preventing or delaying recurrence. The aim of this prospective randomized study was to evaluate the effectiveness of capecitabine as a postoperative adjuvant regimen in inhibiting the recurrence of HCC.