Machine learning for individualized prediction of hepatocellular carcinoma development after the eradication of hepatitis C virus with antivirals.

BACKGROUND AND AIMS: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients. METHODS: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients). RESULTS: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online. CONCLUSIONS: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country. IMPACT AND IMPLICATIONS: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system.

Impact of a Novel Digital Therapeutics System on Nonalcoholic Steatohepatitis: The NASH App Clinical Trial.

INTRODUCTION: Management of nonalcoholic steatohepatitis (NASH) is a currently unmet clinical need. Digital therapeutics (DTx) is an emerging class of medicine that delivers evidence-based therapeutic interventions. This study was aimed at investigating the efficacy of DTx in patients with NASH. METHODS: We conducted a multicenter, single-arm, 48-week trial in 19 patients with biopsy-confirmed NASH. All patients received a DTx intervention with a newly developed smartphone application. The primary endpoint was change in the nonalcoholic fatty liver disease activity score (NAS) without worsening of liver fibrosis. The secondary endpoints included improvement of the NAS by ≥2 points without worsening of liver fibrosis, change in the body weight, and regression of fibrosis. RESULTS: After the 48-week DTx intervention, improvement of the NAS was observed in 68.4% (13/19) of patients. The mean change in the NAS from baseline to the end of the intervention was -2.05 ± 1.96 ( P < 0.001 when compared with the threshold of -0.7). A decrease in the NAS by ≥ 2 points was achieved in 11 (57.9%). The average weight loss at the end of the intervention was 8.3% ( P < 0.001). Reduction of the fibrosis stage was observed in 58.3% when the analysis was limited to patients with stage F2/3 fibrosis. There were no serious adverse events that could be considered as being related to the DTx intervention. DISCUSSION: DTx for NASH was found to be highly efficacious and well-tolerated. Further evaluation of the DTx intervention for NASH in a phase 3 trial is warranted.

A study on prevention of bleeding complications using lusutrombopag for safe RFA in patients with hepatocellular carcinoma with low platelet counts: prospective observational study.

BACKGROUND: Platelet (PLT) transfusion was the most practical way to increase patients' PLT counts before invasive hepatic procedures such as radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). A novel drug that raises the PLT count by acting on the thrombopoietin receptor has recently become available. METHODS: Lusutrombopag 3 mg was administered daily for 7 days to patients who underwent RFA for liver tumors with low PLT counts (< 50,000 PLT µL- 1). We collected demographic data concerning the patients' liver function and PLT counts. RESULTS: Lusutrombopag was administered to 91 patients, with a median age of 71 years (range 51-86). Forty-two patients had hepatitis C, 12 had hepatitis B, 21 had alcoholic liver disease, 11 had nonalcoholic steatohepatitis, and five had other diseases. The median Child-Pugh score was 7 (range 5-11). Thirty-seven patients had stage I tumors, 41 had Stage II, 12 had stage III, and one had stage IV. PLT count was elevated from 4.4 × 104 ± 1.4 × 104 to 8.6 × 104 ± 2.5 × 104 PLT µL- 1. Lusutrombopag administration prevented PLT transfusions in 84/91 patients (92%). No patient had bleeding complications after RFA. One had portal thrombosis after lusutrombopag administration. Patients who achieved PLT counts of > 50,000 PLT µL- 1 had higher PLT counts before lusutrombopag administration. The degree of splenomegaly did not affect the rate of PLT count elevation. There was no specific adverse effect by administrating lusutrombopag for patients with PLT counts of around 50,000 µL- 1 but > 50,000 µL- 1. CONCLUSIONS: Lusutrombopag administration before RFA was effective and seemed to be relatively safe for hepatocellular carcinoma patients with low PLT counts. TRIAL REGISTRATION: This study was approved by Japanese Red Cross Medical Center Institutional Reseach Comittie (#862, 07/03/2016), and was registered in a publically accessible primary register (#UMIN000046629, registered date: 14/01/2022).

Effectiveness of direct acting antiviral agents for hepatitis C virus related recurrent hepatocellular carcinoma patients who had multiple courses of recurrence.

Eradication of hepatitis C virus (HCV) using direct acting antiviral agents (DAAs) has been reported to alter liver function and reduce the recurrence rate after curative treatment in naïve hepatocellular carcinoma (HCC) patients. However, it is not well known whether administration of DAAs had favourable effect on HCC patients with multiple courses of recurrence. We retrospectively extracted 146 HCV-related HCC (C-HCC) patients who received curative treatment using radiofrequency ablation (RFA) followed by eradication treatment with DAA between 1 January 2015 and 31 December 2017. We also extracted 184 C-HCC patients who were curatively treated using RFA without HCV eradication treatment between 1 January 2009 and 31 July 2014 as controls. We used propensity score matching method and adjusted following factors between the 2 groups: age, sex, liver function, number of recurrence times, tumour diameter and tumour numbers. We finally enrolled 47 C-HCC patients with eradication of HCV, and 47 C-HCC patients without HCV eradication as controls. Primary end point was time to curative treatment failure. We defined time to curative treatment failure as the interval from curative treatment initiation to premature discontinuation of this type of therapy. Their clinical data, time to curative treatment failure and overall survival were compared. We also assessed the prognostic values of time to curative treatment failure and overall survival using multivariate Cox proportional hazard models. The median age was 74.8 years, 60 patients (63.8%) were male, and 81 patients (86.2%) were Child-Pugh class A. The median tumour number was 1, tumour diameter was 20 mm, and frequency of recurrence was 3 times. There were no significant differences about patients' backgrounds between the 2 groups. The cumulative time to curative treatment failure rates of patients who received DAA were 93.6% and 73.2% at 1 and 3 years, respectively; those of controls were 72.5%, and 37.1% (p < .01). Multivariate analysis indicated that eradication with DAAs (HR 0.23, 95% CI; 0.12-0.43, p < .01) and DCP >50 mAU/ml (HR 2.62, 95% CI; 1.45-4.74, p < .01) as independent factors contributed to time to curative treatment failure. The cumulative overall survival rates of patients who received DAAs were 93.6% and 72.6% at 1 and 3 years, respectively; those of controls were 72.8% and 37.4% (p < .01). Multivariate analysis indicated that eradication with DAAs (HR 0.32, 95% CI; 0.17-0.60, p < .01) and frequency of recurrence times (HR 1.20 per 1 time, 95% CI; 1.01-1.42, p = .038) as independent factors related to overall survival. Eradication of HCV using DAAs prolonged not only time to curative treatment failure but also overall survival even in C-HCC patients with multiple courses of recurrence.

Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals.

BACKGROUND AND AIMS: It remains unclear whether obesity increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C who achieved a sustained virological response (SVR) with antiviral therapy. METHODS: In this multicenter cohort study, we enrolled patients with chronic hepatitis C who achieved SVR with interferon (IFN)-based therapy (IFN group) or direct-acting antiviral (DAA) therapy (DAA group) between January 1, 1990, and December 31, 2018. The patients underwent regular surveillance for HCC. Cumulative incidence of and the risk factors for HCC development after SVR were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis, respectively. RESULTS: Among 2,055 patients (840 in the IFN group and 1,215 in the DAA group), 75 developed HCC (41 in the IFN group and 34 in the DAA group) during the mean observation period of 4.1 years. The incidence rates of HCC at 1, 2, and 3 years were 1.2, 1.9, and 3.0%, respectively. Multivariate analysis revealed that in addition to older age, lower albumin level, lower platelet count, higher alpha-fetoprotein level, and absence of dyslipidemia, obesity (body mass index ≥25 kg/m2) and heavy alcohol consumption (≥60 g/day) were independent risk factors for HCC development, with adjusted hazard ratio (HR) of 2.53 (95% confidence interval [CI]: 1.51-4.25) and 2.56 (95% CI: 1.14-5.75), respectively. The adjusted HR was not significant between the 2 groups (DAA vs. IFN; HR 1.19, 95% CI: 0.61-2.33). CONCLUSIONS: Obesity and heavy alcohol consumption increased the risk of HCC development after SVR.

Impact of Adverse Events on the Progression-Free Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study.

BACKGROUND AND OBJECTIVE: Experience of the use of lenvatinib (LEN) in the clinical setting remains limited. We conducted this study to elucidate the factors associated with progression-free survival (PFS) in patients with advanced HCC treated with LEN. METHODS: In this multicenter retrospective study, we analyzed data on patient characteristics, treatment outcomes, and adverse events (AEs) for 77 patients with advanced hepatocellular carcinoma (HCC). We also analyzed PFS and factors that influence PFS. RESULTS: The response rate to LEN was 29.9% and the disease control rate was 77.9%. Patients who achieved relative dose intensities of more than 70% had better outcomes (response rate 45.2% vs. 11.4%, P < 0.01). Appetite loss, fatigue, diarrhea, hypertension, and thyroid dysfunction were the most frequent AEs. Twenty-three patients (29.9%) had grade 3 or 4 AEs. Fifty-two patients (67.5%) required a dose reduction and 47 (61.0%) stopped taking the drug due to AEs. The PFS rates at 3, 6, and 12 months were 81.2%, 49.8%, and 34.8%, respectively. The median PFS was 5.6 months. Multivariate analysis showed that thyroid dysfunction of grade ≥ 2 (hazard ratio [HR] 4.57, 95% confidence interval [CI] 2.05-10.2, P < 0.01), appetite loss (HR 3.58, 95% CI 1.72-7.52, P < 0.01), and tumor diameter ≥ 40 mm (HR: 2.27, 95% CI 1.17-4.40, P = 0.015) were independent factors associated with poor PFS. On the other hand, Child-Pugh class 5A (HR 0.41, 95% CI 0.19-0.90, P = 0.027) and complete or partial response (HR 0.40, 95% CI 0.17-0.95, P = 0.039) were independent factors associated with better PFS. CONCLUSIONS: Thyroid dysfunction and appetite loss after the administration of LEN were independent factors associated with shorter PFS, so these AEs should be carefully managed after administering LEN.

[A patient with recurrent sigmoid colon cancer in whom pleural effusion and ascites resolved after FOLFOX 4 therapy].

We performed combination therapy with oxaliplatin/l-LV/5-FU (FOLFOX 4) in a patient with recurrent colorectal cancer (a 58-year-old man) who had pleural effusion and ascites. This resulted in disappearance of the pleural effusion and ascites, as well as negative tumor markers. Surgery was performed for sigmoid colon cancer on September 29, 2004. In February 2006, abdominal swelling was observed, and CEA increased to 15 ng/mL with multiple intraabdominal tumor nodules. The patient was diagnosed as having peritonitis carcinomatosis associated with recurrent sigmoid colon cancer, and was treated with FOLFOX 4. CEA was 134.9 ng/mL before treatment, but became negative after six courses, while his pleural effusion and ascites disappeared after 10 courses of treatment. This treatment also appeared to be useful for recurrent colorectal cancer with peritoneal dissemination.

Age-related comparison of the profiles of patients with hepatocellular carcinoma.

BACKGROUND/AIMS: It is not known whether the putative etiologic factors and clinical and pathological features of hepatocellular carcinoma differ between young adults and older patients. Therefore this study aims to evaluate whether the clinicopathological features in young patients with HCC significantly differ from those of elderly patients. METHODOLOGY: A total of 1014 consecutive patients with HCC were divided into two groups based on age. Among them, 73 patients younger than 50 years of age comprised the first group and 941 patients 50 years and older made up the second. Clinical, laboratory, and pathological characteristics were compared between the two age groups. RESULTS: The male: female ratio and the incidence of positive hepatitis B surface antigen were significantly higher in young patients than in elderly patients. Tumor size, pathological grading of the tumor, and the severity of liver disease did not differ between the two groups. Especially in those patients demonstrating positive antibody to hepatitis C virus, alanine aminotransferase was higher in the younger, and platelet count was lower. Younger patients also had a higher ratio of alcohol consumption compared to elderly patients. CONCLUSIONS: There were age-related differences in the clinicopathological characteristics of HCC patients. Concerning hepatocarcinogenesis, male and HBsAg positive patients were at high risk in young. Of the HCV-related HCC patients, heavy drinking may accelerate the progression from chronic hepatitis to cirrhosis and HCC.

A new method for insertion of long intestinal tube for small bowel obstruction: Nonendoscopic over-the-wire method via short nasogastric tube.

It is often difficult to insert a long intestinal tube (LT) in patients with small bowel obstruction (SBO). We developed a novel technique for inserting an LT without endoscopy called nonendoscopic over-the-wire method via short nasogastric tube (NEWSt). We evaluated the efficacy and safety of NEWSt.We performed a retrospective study of patients who underwent LT insertion for SBO without any indications of strangulation with either NEWSt (n = 16) or endoscopy (n = 17) between November 2011 and February 2015 at our hospital. Univariate analysis was used to assess the success rate of LT placement beyond the duodenojejunal flexure, time required for the procedure, clinical outcomes, and adverse events.The success rate was 100% in both groups. Procedure time was numerically, but not statistically, shorter in the NEWSt group compared with the endoscopy group (24 ±â€Š13 vs 30 ±â€Š13 min; P = 0.174). There were no statistically significant differences between the 2 groups in terms of surgery rate (31% vs 12%; P = 0.225), fasting period (11.3 ±â€Š6.3 vs 9.9 ±â€Š4.5 days; P = 0.482), hospital stay (26.4 ±â€Š22.1 vs 18.7 ±â€Š7.0 days; P = 0.194), and recurrence rate (19% vs 24%; P = 1.0). No serious adverse event was observed in the NEWSt group, whereas serious aspiration pneumonia was observed in 2 patients after LT insertion in the endoscopy group.Without endoscopy, NEWSt enabled the high success rate and the short procedure time for the LT insertion. Prospective, randomized controlled trials are needed.

Analysis of factors influencing hepatocellular carcinoma detection: efficient use of computed tomography during arterial portography and during hepatic arteriography.

BACKGROUND: This study was performed to investigate the situations in which computed tomography (CT) combined with arterial portography and hepatic arteriography surpassed dynamic CT in the detection of hepatocellular carcinoma. METHODS: Computed tomography combined with arterial portography and hepatic arteriography was performed on 137 patients with chronic hepatitis (92 men and 45 women; mean age, 66.5 years) with hepatocellular carcinoma (HCC) as revealed or suspected by dynamic CT. We analyzed the clinical factors leading to the discovery of additional HCC lesions on CT combined with arterial portography and hepatic arteriography that were undetected by dynamic CT. RESULTS: Computed tomography combined with arterial portography and hepatic arteriography detected additional HCC lesions that had not been revealed by dynamic CT in 33 of 137 patients. Univariate analysis revealed that in the event of HCC recurrence (vs. primary), multiple HCC lesions detected by dynamic CT (vs. single) and decreased liver function (Child's classification B/C vs. A) significantly favored the additional detection of HCC lesions. Multivariate logistic regression indicated that recurrence was the strongest predicting factor for finding additional lesions on computed tomography combined with arterial portography and hepatic arteriography. CONCLUSIONS: Computed tomography combined with arterial portography and hepatic arteriography is capable of finding additional HCC lesions undetectable by dynamic CT, especially in advanced cases such as HCC recurrence, which may affect the choice of treatment.

Factors predisposing to poorly differentiated hepatocellular carcinoma and its recurrence.

BACKGROUND/AIMS: We investigated the clinical factors predisposing moderately or poorly differentiated hepatocellular carcinoma and analyzed which clinical and histological factors are associated with poorly differentiated hepatocellular carcinoma (HCC) recurrence. METHODOLOGY: Percutaneous fine-needle biopsy was taken from the liver tumor of 191 consecutive patients between January 1994 and September 1996. The histological degree of differentiation of hepatocellular carcinoma at the first time of initial treatment and at the time of second recurrence was classified according to the criteria of Edmondson and Steiner. RESULTS: At the time of the first therapy, 86 patients, 81, 24, and 0 patients had liver tumors classified as Edmondson (Ed), 1, 2, 3, and 4, respectively. The prognosis of patients with Ed-3/4 HCC was worse than and the tumor sizes were larger than that of Ed-1/2 HCC patients. Of the 167 patients classified as Ed-1/2 at the time of first therapy, HCC recurred in 95 of the patients during the mean follow-up period of 3.4 years. Multivariate analysis revealed that only tumor size (P=0.035) and TACE therapy (P=0.0009) were independently significant factors in predicting future Ed-3/4 or multiple HCC recurrence. CONCLUSIONS: Tumor size and TACE therapy were clinical predisposing factors for Ed-3/4 or multiple HCC recurrences.

Congenital absence of portal vein with multiple hyperplastic nodular lesions in the liver.

Congenital absence of the portal vein is an extremely rare anomaly, in which enteric blood bypasses the liver and drains into the inferior vena cava. A 16-year-old girl was referred to our hospital presenting with liver tumor. Although she had suffered from galactosemia soon after birth, the galactosemia had improved spontaneously 1 year later. Between the ages of 8 and 12 years, chronic hepatitis with a mild elevation of aspartate transaminase (AST) and alanine transaminase (ALT) was observed, but liver tumor had not been detected on computed tomography (CT) in regular medical examinations. However, at age 16, liver tumors, 10 cm in diameter, were found. Abdominal angiography indicated complete absence of the portal vein, suggesting that enteric blood was bypassing the liver and draining into the inferior vena cava. In biopsy specimens obtained under ultrasonographic guidance, liver tumors were confirmed histologically as hyperplastic nodules. In addition to this case report, the clinical features of 25 reported cases of congenital absence of the portal vein are reviewed.

Neither hepatitis C virus genotype nor virus load affects survival of patients with hepatocellular carcinoma.

OBJECTIVE: Hepatitis C virus (HCV) genotype and virus load, the strongest determinants of the efficacy of interferon therapy, have been presumed to be associated with risk for hepatocellular carcinoma (HCC). This study was conducted to elucidate whether these two factors are capable of predicting the prognosis of patients with HCC. METHODS: A total of 371 patients with HCV infection (258 men and 113 women; median age, 66 years; range, 37-88 years) who developed HCC between January 1993 and December 1999 were enrolled. Overall survival and recurrence-free survival were analysed with the Cox proportional hazard regression according to HCV genotype (type 1 versus type 2) and virus load (above versus below 100 kIU/ml). RESULTS: Of the 371 patients, 346 received locoregional treatments (ethanol injection, microwave, radiofrequency, or surgery), and 307 achieved complete response as determined by subsequent imaging studies. The remaining 25 patients underwent arterial embolization or chemotherapy. Cox proportional hazard regression showed that neither genotype (P = 0.814) nor virus load (P = 0.958) were significant predictors for survival (P = 0.814 and 0.958, respectively) and recurrence (P = 0.505 and 0.736, respectively). CONCLUSIONS: Neither genotype nor virus load of HCV affected prognosis of HCC patients.

Clinical features of patients with HCC who are negative for both HBV and HCV markers.

BACKGROUND/AIMS: The aim of this study is to clarify the clinical features of hepatocellular carcinoma that are negative for both hepatitis B surface antigen and anti-hepatitis C antibody. METHODOLOGY: Patients were classified according to viral markers: 45 patients (82%) had hepatitis B (B-HCC), 467 patients (82%) had hepatitis C (C-HCC), and 53 patients (9%) had neither hepatitis B nor hepatitis C (NBNC-HCC). Differences in clinical parameters among these three groups were analyzed. RESULTS: Patients with NBNC-HCC were older than B-HCC and C-HCC patients. The incidence of alcoholism in NBNC-HCC patients was higher than in C-HCC patients. Patients with NBNC-HCC had similar rates of positive antibody to hepatitis B core antigen as did patients with C-HCC. NBNC-HCC patients were further classified according to median age. The younger group showed a greater tendency towards alcoholism than did the aged group. Liver functioning in the younger group was worse than in the older group. The older group had larger tumors than the younger group. CONCLUSIONS: The livers of younger NBNC-HCC patients were more cirrhotic, possibly because of alcoholism. Older NBNC-HCC patients presented with larger tumors, possibly because they did not receive regular medical check-ups due to their relatively preserved liver function.

Changes in hepatic functional reserve after percutaneous tumor ablation for hepatocellular carcinoma: long-term follow up for 227 consecutive patients with a single lesion.

BACKGROUND/AIMS: Percutaneous tumor ablation (PTA), such as ethanol injection, is currently accepted as a potentially curative treatment for hepatocellular carcinoma (HCC). Percutaneous tumor ablation is presumed to be relatively non-invasive, but there are few studies on long-term follow-up of liver function after tumor ablation. METHODS: Changes in liver functions were monitored in 227 consecutive patients treated for a solitary HCC nodule by PTA between 1993 and 1997. The liver function evaluated based on Child-Turcotte classification prior to the initial treatment was Child A in 119 (52.4%) patients, B in 81(35.7%), and C in 27 (11.9%). The follow-up period was 46 +/- 21 months. RESULTS: The five-year survival rates of patients in Child A, B, and C group after treatment were respectively 76%, 45%, and 43%. Annual shift rate of Child A to Child B was 7%, and that of Child B to Child C was 14%. Tumor recurrence significantly affected aggravation of liver function in Child A (P = 0.002) but not in Child B patients (P = 0.55). Tumor size at initial treatment influenced changes of liver function in Child B group patients (P = 0.009). CONCLUSIONS: Preservation of liver function may be essential when treating HCC patients with impaired liver function.

Health-related quality of life of chronic liver disease patients with and without hepatocellular carcinoma.

BACKGROUND AND AIM: Impaired health-related quality of life has been reported in patients with cirrhosis and chronic hepatitis. However, only limited data are available concerning the influence of hepatocellular carcinoma. METHODS: Health-related quality of life was assessed in 97 patients with hepatocellular carcinoma who had been treated successfully with percutaneous ablation therapy, and 97 patients with chronic liver disease without hepatocellular carcinoma matched for age and sex, using the Japanese version of Short-Form 36. Raw scores were transformed using norm-based scoring. The relations with objective variables including status of hepatocellular carcinoma and laboratory data were analyzed. RESULTS: Health-related quality of life was lower in both groups than in the general population. Patients with hepatocellular carcinoma and patients in the control group showed similar scores. By multivariate analysis, liver function, especially serum albumin, strongly predicted health-related quality of life, but status of hepatocellular carcinoma did not. CONCLUSIONS: Impaired health-related quality of life was not associated with the presence of hepatocellular carcinoma but dependent on the level of liver function, indicating the importance of preserving liver function in following up patients. Serum albumin level was a useful objective variable to assess health-related quality of life of patients with chronic liver disease.

Sustained viral response prolonged survival of patients with C-viral hepatocellular carcinoma.

BACKGROUND: We conducted this retrospective study to evaluate the position of interferon therapy in the curative treatment of hepatitis C virus-associated hepatocellular carcinoma (HCC). METHODS: We compared overall and recurrence-free survival rates between 191 patients who received interferon therapy before HCC development (15 with sustained virologic response (SVR)), 53 who received interferon therapy after HCC ablation (17 with SVR), and 399 HCC patients with Child-Pugh class A liver function who did not receive interferon (controls). RESULTS: The overall survival rate in the controls was 82.4%, 53.2%, and 28.3% at 3, 6, and 9 years, respectively, whereas that in patients who developed HCC after achieving SVR was 93.3%, 93.3%, and 93.3%; those with HCC after non-SVR, 87.8%, 56.5%, and 35.8%; SVR after HCC, 100%, 87.5%, and 59.7%; and non-SVR after HCC, 94.3%, 70.9%, and 53.2%. Cox proportional hazard regression analysis revealed that the risk of death was significantly reduced in patients with HCC after SVR and those with SVR after HCC, with a risk ratio of 0.124 (95% confidence interval (95% CI): 0.017-0.890, P = 0.0378) and 0.388 (95% CI: 0.169-0.887, P = 0.0250), respectively, compared with the controls. Improved survival was attributable mainly to sustained liver function among patients with SVR, and recurrence-free survival did not differ significantly. CONCLUSION: Interferon therapies before and after HCC development were both significantly associated with prolonged survival when SVR was achieved.

Prediction of recurrence of hepatocellular carcinoma after curative ablation using three tumor markers.

Three tumor markers for hepatocellular carcinoma (HCC) are available in daily practice in Japan: alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), and lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3). To elucidate the predictability of these tumor markers on HCC recurrence after curative ablation, we enrolled 416 consecutive patients with naïve HCC who had been treated by percutaneous ablation at our department from July 1997 to December 2002. Tumor marker levels were determined immediately before and 2 months after the treatment. Complete ablation was defined on CT findings as nonenhancement in the entire lesion with a safety margin. Tumor recurrence was also defined as newly developed lesions on CT that showed hyperattenuation in the arterial phase with washout in the late phase. We assessed the predictability of recurrence via tumor markers in multivariate analysis, using proportional hazard regression after adjusting for other significant factors in univariate analysis. Until the end of follow-up, tumor recurrence was identified in 277 patients. Univariate analysis revealed the following factors to be significant for recurrence: platelet count; size and number of tumors; AFP, AFP-L3, and DCP preablation; and AFP and AFP-L3 postablation. Multivariate analysis indicated that AFP >100 ng/mL and AFP-L3 >15%, both pre- and postablation, were significant predictors. The positivity of AFP and AFP-L3 preablation that turned negative postablation was not significant. In conclusion, tumor markers pre- and post-ablation were significant predictors for HCC recurrence and can complement imaging modalities in the evaluation of treatment efficacy.

Evaluation of transcatheter arterial embolization prior to percutaneous tumor ablation in patients with hepatocellular carcinoma: a randomized controlled trial.

BACKGROUND: Transcatheter arterial embolization (TAE) may reduce the risk of hepatocellular carcinoma (HCC) recurrence when performed before percutaneous tumor ablation (PTA), either percutaneous ethanol injection therapy (PEIT) or radiofrequency ablation (RFA). We conducted a randomized, controlled trial comparing the use of TAE combined with percutaneous ethanol injection therapy (TAE/PEIT) to the use of PEIT only to assess the effects on HCC recurrence and survival. We continued the study after the introduction of RFA and compared TAE combined with RFA (TAE/RFA) with RFA only. METHODS: Between March 1997 and April 2001, 42 HCC patients were enrolled who satisfied the following inclusion criteria: (1) uninodular HCC as determined by angiography under computed tomography, (2) arterial hypervascularity, and (3) no prior history of HCC treatment. Twenty-two patients were treated with TAE/PTA (PEIT, 12; RFA, 10) and 20 patients with PTA only (PEIT, 14; RFA, 6). RESULTS: There were four cases of local recurrence in the PTA-only group and none in the TAE/PTA group (P=0.043). The four patients with local recurrence were treated with PEIT. None of the patients treated with RFA showed local recurrence. The effect of TAE on overall recurrence was not significant (P=0.4179). In the multivariate analysis, prior TAE was not significant for survival (P=0.514). CONCLUSIONS: TAE has a limited use in suppressing local recurrence when performed before PEIT but not before RFA.