Preoperative difficulty assessment of interval laparoscopic cholecystectomy for gallstones.

BACKGROUND: Laparoscopic cholecystectomy is the gold standard treatment for benign gallbladder disease. However, few studies have reported the difficulty of interval cholecystectomy after cholecystitis because early cholecystectomy is recommended for acute cholecystitis. In this study, we evaluated the difficulties associated with interval cholecystectomy for cholecystitis with gallstones. METHODS: We retrospectively analyzed patients with gallstones who underwent interval laparoscopic cholecystectomy for cholecystitis at our institution between January 2012 and December 2021. Patients were classified into laparoscopic total cholecystectomy and bailout procedure groups depending on whether they were converted to a bailout procedure, and their characteristics and outcomes were subsequently compared. Additionally, a logistic regression analysis of the preoperative factors contributing to bailout procedure conversion was performed. RESULTS: Of the 269 participants, 39 converted to bailout procedure, and bile duct injury occurred in one case (0.4%). In patient characteristics comparison, patients in the bailout procedure group were significantly older, had more impacted stones, had higher post-treatment choledocholithiasis, had severe cholecystitis, and had a higher rate of percutaneous transhepatic gallbladder drainage. There were no differences in the bile duct injury or perioperative complications between the two groups. In logistic regression multivariate analysis of the factors contributing to the bailout procedure, post-treatment of choledocholithiasis (P < .001), impacted stone (P = .002), and age ≥71 (P = .007) were independent risk factors. CONCLUSION: Impacted stones and choledocholithiasis are risk factors for conversion to bailout procedure and high difficulty in interval cholecystectomy. For such patients, interval cholecystectomy should be performed cautiously.

Recurrent Primary Abdominal Wall Abscess: A Case Report and Review of the Literature.

Primary abdominal wall abscess is extremely rare and difficult to diagnose because abdominal wall abscesses usually occur secondary to malignant tumors or inflammatory diseases. We experienced a case of an 80-year-old man with an asynchronous primary abdominal wall abscess with recurrence. Both abscesses were successfully treated with surgical drainage. A patient without any history of cancer or trauma presented to our department with right upper abdominal pain. His laboratory data showed an abnormal high inflammatory response, and computed tomography revealed a 40 × 30 mm mass formed in the rectus abdominis muscle of the upper right abdomen. The mass had no continuity with the surgical scar after cholecystectomy or intra-abdominal organs. Citrobacter diversus was detected in the culture from the mass and any epithelial components were not detected by biopsy. For the diagnosis of primary abdominal wall abscess, the patient underwent surgical drainage because antibiotic treatment was ineffective. The abscess disappeared promptly after the drainage. Thirteen months after the first treatment, another primary abdominal wall abscess was noted in the lower right abdomen. The abscess also promptly disappeared with surgical drainage. Primary abdominal wall abscess is difficult to diagnose because of its rarity. Prompt diagnosis and drainage are important to prevent exacerbation.

Usefulness of Preoperative Predictors of Pathological Complicated Appendicitis.

INTRODUCTION: Complicated appendicitis (CA) is often indicated for emergency surgery; however, preoperative predictors of pathological CA (pCA) remain unclear. Furthermore, characteristics of CA that can be treated conservatively have not yet been established. METHODS: 305 consecutive patients diagnosed with acute appendicitis were reviewed. The patients were divided into two groups: an emergency surgery and a conservative treatment group. The emergency surgery group was pathologically classified as having uncomplicated appendicitis (pUA) and pCA, and the preoperative predictors of pCA were retrospectively assessed. Based on the preoperative pCA predictors, a predictive nomogram whether conservative treatment would be successful or not was created. The predictors were applied to the conservative treatment group, and the outcomes were investigated. RESULTS: In the multiple logistic regression analysis of the factors contributing to pCA, C-reactive protein ≥3.5 mg/dL, ascites, appendiceal wall defect, and periappendiceal fluid collection were independent risk factors. Over 90% of cases without any of the above four preoperative pCA predictors were pUA. The accuracy of the nomogram was 0.938. CONCLUSION: Our preoperative predictors and nomogram are useful to aid in distinguishing pCA and pUA and to predict whether or not conservative treatment will be successful. Some CA can be treated with conservative treatment.

Therapeutic strategy for acute appendicitis based on laparoscopic surgery.

PURPOSE: The treatment strategies for acute appendicitis differ depending on the facility, and various studies have investigated the usefulness of conservative treatment with antibiotics, laparoscopic surgery, and interval appendectomy (IA). However, although laparoscopic surgery is widely used, the clinical strategy for acute appendicitis, especially complicated cases, remains controversial. We assessed a laparoscopic surgery-based treatment strategy for all patients diagnosed with appendicitis, including those with complicated appendicitis (CA). METHODS: We retrospectively analysed patients with acute appendicitis treated in our institution between January 2013 and December 2021. Patients were classified into uncomplicated appendicitis (UA) and CA groups based on computed tomography (CT) findings on the first visit, and the treatment course was subsequently compared. RESULTS: Of 305 participants, 218 were diagnosed with UA and 87 with CA, with surgery performed in 159 cases. Laparoscopic surgery was attempted in 153 cases and had a completion rate of 94.8% (145/153). All open laparotomy transition cases (n = 8) were emergency CA surgery cases. No significant differences were found in the incidence of postoperative complications in successful emergency laparoscopic surgeries. In univariate and multivariate analyses for the conversion to open laparotomy in CA, only the number of days from onset to surgery ≥ 6 days was an independent risk factor (odds ratio: 11.80; P < 0.01). CONCLUSION: Laparoscopic surgery is preferred in all appendicitis cases, including CA. Since laparoscopic surgery is difficult for CA when several days from the onset have passed, it is necessary that surgeons make an early decision on whether to operate.

Validation of Kinki Criteria, a Modified Substaging System, in Patients with Intermediate Stage Hepatocellular Carcinoma.

BACKGROUND: The standard treatment option that is available for patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) is transarterial chemoembolization (TACE). However, the condition of the patients with BCLC stage B disease is heterogeneous showing different tumor statuses and Child-Pugh scores; treatment strategies other than TACE are frequently employed for the patients in this stage. Based on the subclassification system proposed by Bolondi et al. [Semin Liver Dis 2012;32:348-359], we developed the Kinki criteria focusing on a substaging for BCLC stage B disease, which is simpler and should be more suitable in actual clinical setting in Japan. In this study, we evaluated the performance of Kinki criteria. SUMMARY: This study included 1,633 HCC patients who received first-line treatment at the Kindai University Hospital. Patients were classified into subgroups based on the Kinki criteria and the survival time was estimated for each group. There were 156 (33.3%) patients in subclass B1, 278 (59.3%) in B2, and 35 (7.4%) in B3. The median overall survival times and 95% CI for BCLC B subclasses B1, B2, and B3 were 4.3 years (3.7-4.9), 2.9 years (2.2-3.4), and 1.1 years (0.5-1.8), respectively (p < 0.001). Key Messages: Classification of HCC patients in BCLC stage B based on the Kinki criteria showed statistically significant differences in survival, indicating the performance of Kinki criteria, which takes Child-Pugh score and tumor status into account for determining treatment options for HCC in BCLC stage B.

Kupffer phase image of Sonazoid-enhanced US is useful in predicting a hypervascularization of non-hypervascular hypointense hepatic lesions detected on Gd-EOB-DTPA-enhanced MRI: a multicenter retrospective study.

BACKGROUND: It remains unknown whether Kupffer-phase images in Sonazoid-enhanced ultrasonography (US) can be used to predict hypervascularization of borderline lesions. Therefore, we aimed to clarify whether Kupffer-phase images in Sonazoid-enhanced ultrasonography can predict subsequent hypervascularization in hypovascular borderline lesions detected on hepatobiliary-phase gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging. METHODS: From January 2008 to March 2012, 616 low-intensity hypovascular nodules were detected in hepatobiliary-phase images of Gd-EOB-DTPA-enhanced MRI at nine institutions. Among these, 167 nodules, which were confirmed as hypovascular by Gd-EOB-DTPA-enhanced MRI and Sonazoid-enhanced US, were evaluated in this study. Potential hypervascularization factors were selected based on their clinical significance and the results of previous reports. The Kaplan-Meier model and log-rank test were used for univariate analysis and the Cox regression model was used for multivariate analysis. RESULTS: The cumulative incidence of hypervascularization of borderline lesions was 18, 37, and 43 % at 1, 2, and 3 years, respectively. Univariate analyses showed that tumor size (p = 0.0012) and hypoperfusion on Kupffer-phase images in Sonazoid-enhanced US (p = 0.004) were associated with hypervascularization of the tumor. Multivariate analysis showed that tumor size [HR: 1.086, 95 % confidence interval = 1.027-1.148, p = 0.004] and hypo perfusion on Kupffer-phase images [HR: 3.684, 95 % confidence interval = 1.798-7.546, p = 0.0004] were significantly different. CONCLUSIONS: Kupffer-phase images in Sonazoid-enhanced US and tumor diameter can predict hypervascularization of hypointense borderline lesions detected on hepatobiliary-phase Gd-EOB-DTPA-enhanced MRI.

Evaluation of ART Scores for Repeated Transarterial Chemoembolization in Japanese Patients with Hepatocellular Carcinoma.

OBJECTIVE: Transarterial chemoembolization (TACE) is recommended as a first-line therapy for hepatocellular carcinoma (HCC) patients ineligible for curative therapy and without portal invasion. The Assessment for Retreatment with TACE (ART) scoring system was recently proposed for identifying patients who would not show sufficient survival benefit from repeated TACE. We reevaluated the performance of ART in HCC patients treated in Japan, where selective TACE is commonly used. METHODS: Between 2000 and 2013, 988 patients with HCC underwent TACE at Kinki University Hospital, and 627 received ≥2 sessions of TACE. Seventy-six patients who underwent ≥2 TACE sessions within 90 days were investigated for their performance of the ART score in the context of overall survival (OS). RESULTS: Only 12% (76/627) of patients underwent ≥2 TACE sessions within 90 days. Of those, 52 patients showed a low ART score (0-1.5), and 24 had a high ART score (≥2.5); the median OS was 20.2 and 37.6 months, respectively (p = 0.8207). CONCLUSION: The ART scoring system did not demonstrate a sufficiently predictive impact on OS among the patients who underwent ≥2 TACE sessions within 90 days. Application of the ART score should be carefully considered because differences in TACE procedures and post-TACE treatment can affect the results while evaluating OS.

Validation of a Modified Substaging System (Kinki Criteria) for Patients with Intermediate-Stage Hepatocellular Carcinoma.

INTRODUCTION: Barcelona Clinic Liver Cancer (BCLC) stage B, an intermediate stage, includes various conditions of hepatocellular carcinoma (HCC). This heterogeneity of the patients with intermediate-stage HCC makes it difficult to predict their survival rates. In the present study, we examined the validity of the modified Bolondi classification (Kinki criteria) as a subclassification of patients with BCLC stage B HCC. METHODS: Of 906 patients who underwent conventional transarterial chemoembolization at Kinki University Hospital, 753, who met the inclusion criteria, were examined. Of these 753 patients, 425 (56.4%) with BCLC stage B were subclassified using the Kinki criteria to examine the survival rate. RESULTS: According to the Kinki criteria, 158 (37.2%) were subclassified into subclass B1, 236 (55.5%) into B2, and 31 (7.3%) into B3. The comparison of the survival rates showed that the median overall survival was 3.9 years (95% CI, 3.2-4.6) in the BCLC subclass B1 group, 2.5 years (95% CI, 2.2-3.1) in the B2 group, and 1.1 years (95% CI, 0.6-1.5) in the B3 group (p < 0.001). CONCLUSION: When the BCLC stage B patients were subclassified according to the Kinki criteria, survival curves were stratified with significant differences, suggesting that the Kinki criteria were suitable for the subclassification of the intermediate-stage HCC patients.

Real-Life Clinical Practice with Sorafenib in Advanced Hepatocellular Carcinoma: A Single-Center Experience Second Analysis.

OBJECTIVES: Sorafenib has become a standard therapy for advanced hepatocellular carcinoma following the demonstration of significant increase in progression-free survival as well as overall survival (OS) in the 2-phase III trials. We examined efficacy and adverse events (AEs) in patients treated with sorafenib over a 6-year period since approval in Japan. METHODS: Two hundred and forty-one patients treated with sorafenib at the Kinki University Hospital were retrospectively analyzed clinically for the factors related to survival periods, tumor response evaluated by the Response Evaluation Criteria In Cancer of the Liver (RECICL) and AEs. RESULTS: OS was 14.3 months. According to the RECICL, the objective response and disease control rates were 18.6% (43 of 241) and 61.1% (137 of 241), respectively. AEs were seen in 77.3% (187 of 241), with Grade 3 or higher in 23.6% (57 of 241). The most frequent AE was hand-foot skin reaction in 109 patients (45.0%), and 28 patients (11.8%) showed Grade 3 or higher. Significant factors contributing to the OS were treatment duration (p = 0.0204), up-to-7 criteria (p = 0.0400), increase of Child-Pugh score (p = 0.0008) and tumor response determined by the RECICL (p = 0.0007). CONCLUSION: Based on the analysis, using many cases at a single center, we concluded that continuation of treatment with sorafenib for ≥90 days without decrease of liver function was critical if tumor response was determined as stable disease or higher.

Comparison between T1 relaxation time of Gd-EOB-DTPA-enhanced MRI and liver stiffness measurement of ultrasound elastography in the evaluation of cirrhotic liver.

PURPOSE: To compare four imaging approaches in cirrhotic estimation; pre-enhancement T1 relaxation time (T1RT), reduction rate (RR) of T1RT, signal-based liver-to-muscle ratio (L/M ratio) on gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), and liver stiffness measurement (LSM) of US elastography. MATERIALS AND METHODS: Consecutive 58 patients with chronic liver diseases who underwent both Gd-EOB-DTPA-enhanced MRI and FibroScan were analyzed. Four imaging approaches were evaluated by fibrosis score from liver biopsy and receiver operating characteristic (ROC) analysis. RESULTS: RR was found to be inversely correlated with LSM (r = -0.65). RR decreased with degree of fibrosis (F0-F1, 58.5 ± 6.2%, versus F2-F3-F4, 48.8 ± 11.7%, P = 0.010, F0-F1-F2, 58.2 ± 6.2% versus F3-F4, 45.5 ± 12.3%, P = 0.010 and F0-F1, 58.5 ± 6.2%, versus F2-F3, 52.1 ± 12.0%, P = 0.0038). LSM increased with degree of fibrosis (F0-F1, 5.4 ± 2.2 kPa versus F2-F3-F3, 19.3 ± 15.5 kPa, P = 0.0011 and F0-F1-F2, 6.8 ± 3.6 kPa versus F3-F4, 23.8 ± 17.1 kPa, P = 0.0029 and F0-F1, 5.4 ± 2.2 kPa, versus F2-F3, 11.4 ± 7.2 kPa, P = 0.0098). Area under ROC curves were 0.83 (F3-F4), 0.72 (F2-F3-F4), 0.68 (F2-F3) for RR and 0.83 (F3-F4), 0.88 (F2-F3-F4), 0.81 (F2-F3) for LSM in discriminating between patients with fibrosis. CONCLUSION: The capability by LSM was better than those by RR of T1RT, pre-enhancement T1RT, and L/M ratio to differentiate F ≥ 2, but LSM and RR of T1RT showed the same value to differentiate F ≥ 3.

Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil.

We conducted a phase I/II study in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose, as well as the safety and efficacy, of combination therapy of sorafenib with hepatic arterial infusion chemotherapy (HAIC) using low dose cisplatin (CDDP) and 5-fluorouracil (5FU). Cohorts consisting of 3-6 patients with HCC received an escalated dose of CDDP and 5-FU until a maximum-tolerated dose was achieved. The treatment regimen was as follows: oral administration of sorafenib (400 mg twice daily for 28 days) combined with HAIC using CDDP (14-20 mg/m(2), on days 1 and 8) and 5-FU (170-330 mg/m(2), continuously on days 1-5 and 8-12) via an implanted catheter system). Each treatment cycle consisted of 28 days and three cycles of combination therapy. At the end of the first cycle, adverse events were evaluated and future dose escalation was determined. Eighteen patients with advanced HCC were enrolled. Dose-limiting toxicity was observed in two patients from cohort 1 (erythema multiforme and grade 4 thrombocytopenia) and in one patient from cohort 2 (erythema multiforme). Seven of the 18 patients achieved a partial response, seven showed stable disease, two were diagnosed as progressive disease, and two were not assessable. The response rate was 38.9% and the disease control rate was 77.8%. The time-to-progression was 9.7 months and the 1-year survival rate was 88.2%. Oral administration of 400 mg of sorafenib twice daily, 20 mg/m(2) of intra-arterial infusion of CDDP, and 5-FU at 330 mg/m(2) are the recommended doses for combination therapy, which was well tolerated and efficacious. This combination therapy may be a promising treatment for patients with advanced HCC. A large prospective randomized multicenter study (ClinicalTrials.gov Identifier NCT01214343) is ongoing.

Effectiveness of Sorafenib in Patients with Transcatheter Arterial Chemoembolization (TACE) Refractory and Intermediate-Stage Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Patients with intermediate-stage hepatocellular carcinoma (HCC) refractory to transcatheter arterial chemoembolization (TACE) are considered to be candidates for sorafenib. The aim of this study was to evaluate the superiority of conversion of treatment to sorafenib on overall survival (OS) for cases refractory to TACE. METHODS: This was a retrospective cohort study carried out on 497 patients with HCC who were treated with TACE therapy at our hospital between January 2008 and December 2013. Fifty-six patients were diagnosed as refractory to TACE during their clinical course and they were divided into two cohorts, (1) those who switched from TACE to sorafenib and (2) those who continued TACE. The overall survival (OS) after the time of being refractory to TACE was evaluated between the two groups. RESULTS: After refractoriness to TACE therapy was confirmed, 24 patients continued with TACE (TACE-group) and 32 patients underwent treatment conversion to sorafenib (sorafenib-group). The median OS was 24.7 months in the sorafenib-group and 13.6 months in the TACE-group (p=0.002). CONCLUSIONS: Conversion to sorafenib significantly improves the OS in patients refractory to TACE therapy with intermediate-stage HCC. Administration of sorafenib is therefore recommended in such circumstances of TACE treatment failure.

Genome-wide profiling of DNA methylation and tumor progression in human hepatocellular carcinoma.

OBJECTIVE: To clarify the progression pattern of abnormal DNA methylation during the development of hepatocellular carcinoma (HCC) using a comprehensive methylation assay. METHODS: We used an Infinium HumanMethylation450 BeadChip array that can analyze >485,000 CpG sites distributed throughout the genome for a comprehensive methylation study of 117 liver tissues consisting of 59 HCC and 58 noncancerous livers. Altered DNA methylation patterns during tumor progression were also analyzed. RESULTS: We identified 38,330 CpG sites with significant differences in methylation levels between HCCs and noncancerous livers (DM-CpGs) using strict criteria. Of the DM-CpGs, 92% were hypomethylated and only 3,051 CpGs (8%) were hypermethylated in HCC. The DM-CpGs were more prevalent within intergenic regions with isolated CpGs. In contrast, DM-CpGs that were hypermethylated in HCC were predominantly located within promoter regions and CpG islands (p < 0.0001). The association between methylation profiles of DM-CpGs and tumor size was statistically significant, especially in hepatitis C virus (HCV)-positive cases (p = 0.0001). CONCLUSIONS: We clarified the unique characteristics of DM-CpGs in human HCCs. The stepwise progression of alterations in DNA methylation was a common feature of HCV-related hepatocarcinogenesis.

Radiofrequency ablation for hepatocellular carcinoma measuring 2 cm or smaller: results and risk factors for local recurrence.

OBJECTIVE: The purpose of this study was to evaluate the risk factors for local recurrence with radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) measuring ≤2 cm. METHODS: This study involved 234 patients with 274 HCCs measuring ≤2 cm who had undergone RFA as the initial treatment. The mean tumor diameter was 1.478 cm. The median follow-up period was 829 days. We evaluated the post-RFA cumulative local recurrence rate and analyzed the risk factors contributing to clinical outcomes. RESULTS: Cumulative local recurrence rates were 9, 19 and 19% at 1, 2 and 3 years, respectively. Among the 145 cases with a complete safety margin (SM) after RFA, only 4 developed local tumor recurrence and the cumulative rates of local tumor recurrence at 1, 2 and 3 years were 2, 3 and 3%, respectively. Among the 129 cases with incomplete SM, local tumor recurrence developed in 34 and the cumulative rates of local tumor progression at 1, 2 and 3 years were 14, 36 and 36%, respectively. In multivariate analysis, significant risk factors were tumor location (liver surface), irregular gross type and SM <5 mm. CONCLUSION: Even with HCC measuring ≤2 cm, location and gross type of tumor should be carefully evaluated before RFA is performed.

Duration of stable disease is associated with overall survival in patients with advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND: Sorafenib is a molecular-targeting agent showing improved overall survival (OS) for advanced hepatocellular carcinoma (HCC). Although tumor dormancy, characterized by stable tumor status or stable disease (SD) without tumor regression, is a unique feature of sorafenib treatment, the contribution of SD to OS remains debatable. This study aimed to clarify the correlation between SD periods and OS in patients with HCC treated with sorafenib. METHODS: From May 2009 to January 2013, 269 patients with advanced-stage HCC were treated with sorafenib at the Kinki University Hospital. The antitumor response of sorafenib was evaluated in 158 patients using the modified Response Evaluation Criteria in Solid Tumors, and patients with SD were divided into two subgroups according to the median duration of SD: short SD (<3 months) and long SD (≥3 months). The relationship between the duration of SD and OS was analyzed among patients with complete (CR) and partial response (PR), and long and short SD using the Kaplan-Meier method. RESULTS: The median OS was 5.7 months in the short SD, 20.8 months in the long SD and 17.9 months in the CR + PR group. Although the duration of OS was significantly longer in the long SD group than the short SD group, no difference in OS was detected between the patients with CR + PR and patients with long SD. The impact of long SD on OS could be as strong as that of CR + PR. CONCLUSION: Achievement of long SD is one of the important goals for improving survival in patients with HCC treated with sorafenib.

Decreased blood flow after sorafenib administration is an imaging biomarker to predict overall survival in patients with advanced hepatocellular carcinoma.

BACKGROUND: Sorafenib is a multikinase inhibitor targeting Raf and protein tyrosine kinases, which are involved in cell growth and tumor angiogenesis. Sorafenib administration induces temporary inhibition of tumor growth and a decrease in arterial blood flow in a considerable number of hepatocellular carcinoma (HCC) patients. We retrospectively evaluated the association between decreased blood flow and the overall survival (OS) of HCC patients after the initiation of sorafenib therapy. PATIENTS AND METHODS: Therapeutic responses of 158 advanced HCC patients with hypervascular tumors who had received sorafenib for more than 1 month were analyzed. To assess their therapeutic response, patients underwent radiological evaluation before and every 4-6 weeks after the initiation of sorafenib treatment. After the classification of patients into three groups based on the change in arterial enhancement during treatment (no change, decrease and disappearance), the OS of each group was compared using the Kaplan-Meier method. RESULTS: Statistically significant differences in OS were observed among the three groups (p < 0.001). A decrease or disappearance of arterial enhancement was significantly associated with improved OS compared to patients with no change in arterial enhancement; the median OS was 19.9 months (95% confidence interval, CI, 16.4-24.5 months) and 6.0 months (95% CI, 4.0-8.8 months), respectively (p < 0.001). However, there was no difference in OS between the decrease and disappearance groups (p = 0.88). CONCLUSION: We conclude that decreased arterial enhancement during sorafenib treatment was associated with the longest OS and could therefore reflect an effective response.

Identification of epigenetically inactivated genes in human hepatocellular carcinoma by integrative analyses of methylation profiling and pharmacological unmasking.

OBJECTIVES: DNA methylation-dependent transcriptional inactivation of tumor suppressor genes (TSGs) is critical for the pathogenesis of hepatocellular carcinoma (HCC). This study identifies potential TSGs in HCCs using methylation profiling and pharmacological unmasking of methylated TSGs. METHODS: Methylation profiling was performed on 22 pairs of HCCs and their corresponding noncancerous liver tissues using the Infinium HumanMethylation27 BeadChip. We also determined the gene reexpression after treatment with 5-aza-2'-deoxycytidine (5-Aza-dC) and trichostatin A (TSA) in 5 HCC cell lines. RESULTS: We selected CpGs that exhibited a significant increase in methylation in HCC tissues compared with that of the noncancerous control group. Two hundred and thirteen CpGs on different gene promoters with a mean difference in the ß value ≥0.15 and a value of p < 0.05 were selected. Of the 213 genes, 45 genes were upregulated in 3 or more HCC cell lines with multiplier value of differences ≥2.0 after 5-Aza-dC and TSA treatment. CONCLUSIONS: We identified several potential TSGs that participate in transcription inactivation through epigenetic interactions in HCC. The results of this study are important for the understanding of functionally important epigenetic alterations in HCC.

Validation of the criteria of transcatheter arterial chemoembolization failure or refractoriness in patients with advanced hepatocellular carcinoma proposed by the LCSGJ.

BACKGROUND: Transcatheter arterial chemoembolization (TACE) failure or refractoriness is an indication for sorafenib therapy in patients with advanced hepatocellular carcinoma. The study evaluated the validity of the definition of TACE failure or refractoriness as proposed by the Liver Cancer Study Group of Japan (LCSGJ) through a retrospective analysis of sorafenib treatment. METHODS: Out of 265 patients with advanced hepatocellular carcinoma who were treated with sorafenib at our hospital, 45 experienced TACE failure or refractoriness and were included in this study and retrospectively analyzed. RESULTS: Multivariate analysis only identified the number of ineffective TACE procedures performed before starting sorafenib treatment as significant factors. Overall survival (OS) after starting sorafenib was statistically longer in patients treated with ≤2 consecutive ineffective TACE procedures before sorafenib administration than in patients treated with ≥3 consecutive ineffective TACE procedures (p < 0.005). This result matched the LCSGJ criteria. CONCLUSION: In patients treated with sorafenib, OS was extended with ≤2 consecutive ineffective TACE procedures compared to that with ≥3 consecutive ineffective TACE procedures. Thus, if tumors are uncontrolled, TACE should not be repeated. The result of this study supports the definition of TACE failure or refractoriness proposed by the LCSGJ.