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AIM:To investigate the treatment strategies and longterm outcomes of radiofrequency ablation(RFA) of hepatocellular carcinoma(HCC) in difficult locations and to compare the results with non-difficult HCC.METHODS:From 2004 to 2012,a total of 470 HCC patients underwent ultrasound-guided percutaneous RFA.Among these HCC patients,382 with tumors located ≤ 5 mm from a major vessel/bile duct(n = 87),from peripheral important structures(n = 232) or from the liver capsule(n = 63) were regarded as difficult cases.There were 331 male patients and 51 female patients,with an average age of 55.3 ± 10.1 years old.A total of 235 and 147 patients had ChildPugh class A and class B liver function,respectively.The average tumor size was 3.4 ± 1.2 cm.Individual treatment strategies were developed to treat these difficult cases.During the same period,88 HCC patients with tumors that were not in difficult locations served as the control group.In the control group,74 patients were male,and 14 patients were female,with an average age of 57.4 ± 11.8 years old.Of these,62 patients and 26 patients had Child-Pugh class A and class B liver function,respectively.Regular follow-up after RFA was performed to assess treatment efficacy.Survival results were generated from Kaplan-Meier estimates,and multivariate analysis was performed using the Cox regression model.RESULTS:Early tumor necrosis rate in the difficult group was similar to that in the control group(97.6% vs 94.3%,P = 0.080).The complication rate in the difficult group was significantly higher than that in thecontrol group(4.9% vs 0.8%,P = 0.041).The followup period ranged from 6 to 116 mo,with an average of 28 ± 22.4 mo.Local progression rate in the difficult group was significantly higher than that in the control group(12.7% vs 7.1%,P = 0.046).However,the 1-,3-,5-,and 7-year overall survival rates in the difficult group were not significantly different from those in the control group(84.3%,54.4%,41.2%,and 29.9% vs 92.5%,60.3%,43.2%,and 32.8%,respectively,P = 0.371).Additionally,a multivariate analysis revealed that tumor location was not a significant risk factor for survival.CONCLUSION:There was no significant difference in long-term overall survival between the two groups even though the local progression rate was higher in the difficult group.