Predictive factors for transition to conversion therapy in hepatocellular carcinoma using atezolizumab plus bevacizumab.

BACKGROUND: To identify predictive factors associated with successful transition to conversion therapy following combination therapy with atezolizumab and bevacizumab in the treatment of unresectable hepatocellular carcinoma (HCC). METHODS: In total, 188 patients with HCC, who received atezolizumab plus bevacizumab combination therapy as the first-line chemotherapy, were studied. Patients who achieved complete response (CR) with systemic chemotherapy alone were excluded. Clinical factors possibly linked to successful transition to conversion therapy and the achievement of cancer-free status were identified. RESULTS: Fifteen (8.0%) patients underwent conversion therapy. In the conversion group, there was a significantly higher proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage A or B (73.3% versus [vs.] 45.1%; p = .03) and tended to have lower Child-Pugh scores and alpha-fetoprotein levels. Multivariate analysis revealed that BCLC stage was a predictive factor for the implementation of conversion therapy (A or B; odds ratio 3.7 [95% CI: 1.1-13]; p = .04). Furthermore, 10 (66.7%) patients achieved cancer-free status and exhibited a smaller number of intrahepatic lesions at the start of treatment (3.5 vs. 7; p < .01), and a shorter interval between systemic chemotherapy induction and conversion therapy (131 vs. 404 days; p < .01). In addition, the rate of achieving cancer-free status by undergoing surgical resection or ablation therapy was significantly higher (p = .03). CONCLUSION: BCLC stage was the sole predictive factor for successful transition to conversion therapy when using combination therapy with atezolizumab and bevacizumab to treat HCC. Furthermore, a small number of intrahepatic lesions and early transition to conversion therapy were associated with the achievement of cancer-free status.

Two cases of perforated duodenal diverticulum successfully treated using conservative therapy.

We encountered two cases of perforated duodenal diverticulum successfully treated with conservative therapy. The first case involved a 72-year-old man who presented with abdominal pain and fever. An abdominal computed tomography revealed pneumoretroperitoneum. The second case involved a 90-year-old woman who presented with abdominal pain, vomiting, and fever. An abdominal computed tomography also revealed pneumoretroperitoneum and fluid collection. In both the cases, we initiated conservative therapy with parenteral nutrition and intravenous antibiotic therapy because the patients' general condition was good and the pneumoretroperitoneum was localized. Both patients were cured without serious complications and were discharged from the hospital 14 days after admission. Conservative treatment may be useful in the patients with early stage of perforated duodenal diverticulum and a good general condition without impending sepsis. However, in case of disease aggravation, careful observation and preparation for immediate surgical drainage are desired.

A case of small intestinal ileus caused by migration of gastric bezoars, which was successfully treated by dissolution therapy with cola through an ileus tube.

A 60-year-old woman with a history of distal gastrectomy for gastric cancer presented with a chief complaint of epigastric pain. Duodenal ileus due to the migration of a gastric bezoar was diagnosed, and she was hospitalized. We performed endoscopic lithotripsy and injection of cola, but the bezoar migrated toward the anus. Her abdominal pain worsened the following day, and she was diagnosed with ileus induced by the gastric bezoar. After decompression with an ileus tube, 1000ml/day of cola was injected via the ileus tube, and the ileus resolved on the 5th day of therapy. Based on this experience, we believe that dissolution therapy with cola via an ileus tube is effective in the treatment of bezoar-induced small bowel ileus.

Entecavir Reduces Hepatocarcinogenesis in Chronic Hepatitis B Patients.

Chronic hepatitis B (CHB) leads to cirrhosis and hepatocellular carcinoma (HCC). With a cohort of 1,206 CHB patients who visited Okayama University Hospital and related hospitals in 2011 and 2012, we compared the incidence rates of HCC among the patients grouped by age, hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg), and treatment. HCCs were observed in 115 patients with the median observation period of 1,687 days. Among the HCC patients aged > 35 years, HBV DNA > 4 log copies/mL and positive HBeAg at diagnosis (n＝184), the HCC incidence rate was 8.4% at 5 years in the entecavir (ETV)-treated patients, 21.8% in the lamivudine (LVD)-treated patients, and 26.4% among the patients not treated with drugs. The cumulative HCC incidence was significantly reduced in the ETV-treated patients compared to those treated with LVD or not treated (p＝0.013). Among the patients aged >35 years with HBV DNA > 4 log copies/mL and negative HBeAg (n＝237), the cumulative HCC incidence was 14.6% in 5 years in ETV group and 13.9% among those not treated with a drug (p＞0.05). Only small numbers of HCCs occurred in other patients. In CHB patients aged > 35 years with HBV DNA > 4 log copies/mL and positive HBeAg, ETV treatment is recommended for the suppression of HCC development.

Local recurrence and complications after percutaneous radiofrequency ablation of hepatocellular carcinoma: a retrospective cohort study focused on tumor location.

We conducted a retrospective cohort study to investigate the predisposing factors for local recurrence and complications after percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). HCC patients (n＝397) consecutively treated with RFA (256 males, 141 females, median age 69 years) were enrolled. In these patients, 1,455 nodules (median size 17mm) were ablated. Predisposing factors for overall recurrence and local recurrence in the context of tumor location and complications were examined. Local recurrence was observed for 113 of the 1,455 nodules. The 1-, 3- and 5-year local recurrence rates were 2.2%, 7.4% and 9.5%, respectively. A multivariate Cox proportional hazard analysis revealed that large tumor size (＞2cm), tumor location (adjacent to the major portal branch or hepatic vein), and small ablated margin (＜3mm) were independent predisposing factors for local recurrence after RFA (HR＝1.70-2.81). Tumor location (adjacent to the major portal branch, hepatic vein, or diaphragm) was also revealed as a risk factor for liver damage due to RFA. HCC adjacent to the major portal vein or hepatic vein was associated with a higher risk for local recurrence and for complications;therefore, special precautions are necessary when applying RFA to HCC near vessels even when the tumors are located at an easy-to-puncture site.

Prevalence and outcomes of acute hepatitis B in Okayama, Japan, 2006-2010.

Hepatitis B virus (HBV) is one of the major viruses causing acute hepatitis. Recently, the incidence of acute hepatitis with genotype A has been increasing in Japan. The aim of this study was to investigate acute hepatitis B (AHB) in Okayama prefecture, with special attention to HBV genotype A. AHB patients who visited one of 12 general hospitals in Okayama prefecture between 2006 and 2010 were retrospectively analyzed. Over the course of the study period, 128 patients were diagnosed with AHB. Sexual transmission was supposed in the majority of patients (78 patients, 61%), including 59 (76%) having sex with heterosexual partners. The genotypes of HBV were assessed in 90 patients (70%), of whom 27 patients were infected with genotype A, 5 with genotype B, and 58 with genotype C. The prevalence of genotype A was significantly higher among male patients (28.7%), aged 20-29 (35.6%, p＜0.01), among men who had sex with men (100%, p＜0.005), and among patients having sex with unspecified partners (44.8%, p＜0.005). Genotype A was not a significant factor associated with delayed HBsAg disappearance. Caution should be exercised with regard to sexually transmissible diseases in order to slow the pandemic spread of AHB due to genotype A.

The diagnosis of hypovascular hepatic lesions showing hypo-intensity in the hepatobiliary phase of Gd-EOB- DTPA-enhanced MR imaging in high-risk patients for hepatocellular carcinoma.

The aim of this study was to evaluate the histologic diagnosis of hypovascular hepatic lesions showing hypointensity on hepatobiliary phase images of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI (EOB-MRI). In 38 patients with hepatocellular carcinoma (HCC) after curative treatments and 18 patients with liver cirrhosis, 105 hypovascular nodules that were hypointense at the hepatobiliary phase of EOB-MRI were biopsied and the clinical usefulness of these EOB-MRI findings for the diagnosis of HCC was examined. Of the 105 nodules (median diameter = 12mm), 78 (74.3%), 11 (10.5%), and 16 (15.2%) were diagnosed as HCC, dysplastic, and non-neoplastic, respectively. The positive predictive value (PPV) of hypointensity at the hepatobiliary phase of EOB-MRI for the diagnosis of HCC increased to 77-90% when combined with the following factors: washout appearance on the delayed phase of triple-phase CT, hyperintensity in diffusion-weighted image of MRI, or the appearance of a hypoechoic part in ultrasonography. PPV increased to 100% when all 3 factors were positive. A relatively large proportion of hypovascular lesions that showed hypo-intensity in the hepatobiliary phase were confirmed to be HCC, and the accuracy of HCC increased when combined with other imaging findings.

Sepsis-associated liver injury: Incidence, classification and the clinical significance.

AIM: Although it is a common complication of sepsis, sepsis-associated liver injury has not been substantially recognized, because its diagnostic criteria and clinical implications are unclear. We aimed to elucidate the incidence, manifestation, disease type classification and prognosis of sepsis-associated liver injury. METHODS: The subjects were 588 patients admitted to our hospital for sepsis between 2001 and 2010. They were classified into "normal liver function", "sepsis-associated liver injury" and "sepsis-not-associated liver injury" groups. Sepsis-associated liver injury was classified as either "cholestatic", "hepatocellular" or "shock liver." Each of these three subgroups was further classified into "with jaundice" or "without jaundice". The primary end-point was the "poor prognosis ratio", defined as the proportion of patients whose prognosis was "unchanged", "worsened" or "died". RESULTS: Among the 449 subjects except for sepsis-not-associated liver injury (n = 139), the incidence of sepsis-associated liver injury was 34.7% (156/449), including 75 cholestatic (48.1%), 34 hepatocellular (21.8%) and 47 shock liver (30.1%) cases. Jaundice was a complication in 25 (33%), six (17.6%) and four (8.5%) patients in each group, respectively. The poor prognosis ratio was higher in males (37.5%) and in the elderly (47.7%); it was 48.0%, 38.2% and 62.8% in the cholestatic, hepatocellular and shock liver groups, respectively, and higher than the normal liver function (18.4%) group (P < 0.0001). It was also higher in patients with jaundice (68.6%) than in those without (45.5%) (P < 0.0001). CONCLUSION: Sepsis-associated liver injury, especially with jaundice, is a significant predictive sign of poor prognosis in patients with sepsis.

Runt-related transcription factor 3 reverses epithelial-mesenchymal transition in hepatocellular carcinoma.

Loss or decreased expression of runt-related transcription factor 3 (RUNX3), a tumor suppressor gene involved in gastric and other cancers, has been frequently observed in hepatocellular carcinoma (HCC). The objective of this study was to identify the regulatory mechanism of the epithelial-mesenchymal transition (EMT) by RUNX3 in HCC. Human HCC cell lines, Hep3B, Huh7, HLF and SK-Hep1, were divided into low- and high-EMT lines, based on their expression of TWIST1 and SNAI2, and were used in this in vitro study. Ectopic RUNX3 expression had an anti-EMT effect in low-EMT HCC cell lines characterized by increased E-cadherin expression and decreased N-cadherin and vimentin expression. RUNX3 expression has previously been reported to reduce jagged-1 (JAG1) expression; therefore, JAG1 ligand peptide was used to reinduce EMT in RUNX3-expressing low-EMT HCC cells. Immunohistochemical analyses were performed for RUNX3, E-cadherin, N-cadherin and TWIST1 in 33 human HCC tissues, also divided into low- and high-EMT HCC, based on TWIST1 expression. E-cadherin expression was correlated positively and N-cadherin expression was correlated negatively with RUNX3 expression in low-EMT HCC tissues. Correlations between EMT markers and RUNX3 mRNA expression were analyzed using Oncomine datasets. Similarly, mRNA expression of E-cadherin was also significantly correlated with that of RUNX3 in low-EMT HCC, while mRNA expression of JAG1 was negatively correlated with that of RUNX3. These results suggest a novel mechanism by which loss or decreased expression of RUNX3 induces EMT via induction of JAG1 expression in low-EMT HCC.

Effect of previous interferon treatment on outcome after curative treatment for hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND AND AIMS: Treatment of chronic hepatitis C virus (HCV) infection with interferon (IFN) prevents the development of hepatocellular carcinoma (HCC). The purpose of this study was to clarify the effect of previous IFN treatment before the development of HCC on recurrence and survival in HCV-related HCC patients. METHODS: Three hundred ninety-five patients who underwent curative treatment for HCV-related HCC were enrolled. Of these, 124 had received IFN treatment before the development of HCC (17 achieved sustained virological response [SVR group] and 107 did not [non-SVR group]), whereas 271 patients had never received IFN treatment (IFN-untreated group). The first and second recurrence and survival rates in these patient groups were statistically analyzed. RESULTS: The first HCC recurrence rate was similar among patient groups. In contrast, the second HCC recurrence rate was significantly lower in the SVR group than in the non-SVR group (p = 0.003) and the IFN-untreated group (p = 0.006). In multivariate analysis, platelet count (p = 0.033) and number of tumors (p = 0.001) were associated with the first HCC recurrence, while SVR (p = 0.002) was the only factor associated with the second HCC recurrence. The survival rate was higher in the SVR group than in non-SVR and IFN-untreated groups, and SVR to previous IFN treatment was an independent factor associated with better survival (p < 0.001). CONCLUSIONS: SVR to previous IFN treatment before the development of HCV-related HCC was associated with lower risk of the second recurrence of HCC and better survival.

Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma.

BACKGROUND AND AIM: Sorafenib, the first agent demonstrated to have efficacy to improve the survival of patients with advanced hepatocellular carcinoma (HCC), is an active multikinase inhibitor affecting angiogenesis and tumor proliferation. We analyzed cytokines related to angiogenesis or cell proliferation, and tried to determine their utility as biomarkers of sorafenib treatment effect for HCC. METHODS: Nine serum cytokines (angiopoietin-2 [Ang-2], follistatin, granulocyte colony-stimulating factor [G-CSF], hepatocyte growth factor [HGF], interleukin-8 [IL-8], leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor) were measured in 30 HCC patients treated with sorafenib, and the effects of treatment were compared using modified Response Evaluation Criteria in Solid Tumors. RESULTS: All but IL-8 were significantly higher at baseline in patients with progressive disease. Progression-free survival was significantly shorter in patients with high levels of Ang-2, G-CSF, HGF, and leptin, and the hazard ratios were 2.51, 6.89, 2.55, and 4.14, respectively. As the number of cytokines at a high level increased, the treatment response deteriorated. Disease progression was seen in three of 12 (25.0%) patients with zero to two high biomarkers, two of six (33.3%) patients with 3-5 high biomarkers, and 10 of 12 (83.3%) patients with six to eight high biomarkers (P=0.008). The prognosis of all patients with eight high biomarkers was progressive disease. CONCLUSION: High levels of serum cytokines at baseline were correlated with poor effects of sorafenib treatment in patients with HCC.

Prognostic importance of fucosylated alpha-fetoprotein in hepatocellular carcinoma patients with low alpha-fetoprotein.

BACKGROUND AND AIM: Fucosylated alpha-fetoprotein (AFP-L3) is known to be a marker of poor prognosis in patients with hepatocellular carcinoma (HCC). However, it has been difficult to measure AFP-L3 under low AFP (≤ 20 ng/mL). The aim of this study was to elucidate the role of AFP-L3 in HCC patients with low AFP conditions. METHODS: One hundred and ninety six consecutive newly developed HCC patients with low AFP (≤ 20 ng/mL) were examined for serum AFP-L3 expression by a newly-developed micro-total analysis system that could stably measure AFP-L3 in low AFP circumstances, and its clinical importance was analyzed. RESULTS: Positivity of AFP-L3 in HCC patients was 13.3% at a cut-off level of 10%. Five-year survivals of HCC patients with AFP-L3 (< 10%) and AFP-L3 (≥ 10%) were 69.4% and 41.1%, respectively (P = 0.001). Among 18 clinical parameters, low alanine aminotransferase, large tumor size, presence of portal vein tumor thrombus, high AFP and high des-gamma carboxy prothrombin were observed in the high AFP-L3 (≥ 10%) group. Multivariate analysis revealed that high aspartate aminotransferase (AST) (risk ratio [RR]= 3.24, 95% confidence interval [CI] = 1.27-8.26), the presence of ascites (RR = 3.44, 95% CI = 1.22-9.34), multiple tumor number (RR= 3.06, 95% CI = 1.33-7.17), and high AFP-L3 (RR = 8.36, 95% CI= 2.79-25.5) were risk factors for survival. High AFP-L3 was also a risk factor for survival in HCC patients who received radiofrequency ablation (P = 0.048). CONCLUSIONS: AFP-L3 is a strong prognostic factor for survival even in HCC patients with low AFP (≤ 20 ng/mL).

Hepatocellular carcinoma occurring in hepatobiliary fibropolycystic disease.

Congenital hepatic fibrosis (CHF) and bile duct hamartomas (von Meyenburg complexes) are hepatobiliary fibropolycystic diseases. There have been several reports of liver neoplasias arising in hepatobiliary fibropolycystic diseases. However, most of them were cholangiocarcinomas and cases involving hepatocellular carcinoma (HCC) are rare. A 51-year-old woman was found to have multiple hepatic tumors by ultrasonography and enhanced computed tomography (CT) during a regular work-up for the recurrence of lung cancer and thyroid cancer, which had been surgically removed 4 and 3 years ago, respectively. Nodules were observed at S3, S5, and S6 (2 cm in diameter). All of the nodules were hyperattenuated at the early arterial phase, and the main tumor at S5 showed hypoattenuation at the delayed phase on dynamic CT and magnetic resonance imaging (MRI). HCC was suspected from these findings. She also suffered from multiple small cystic lesions in the liver. The surgically removed liver showed HCC arising in CHF, which is a rare histological finding.

Prognostic model for hepatocellular carcinoma with time-dependent factors.

The purpose of this study was to build a prognostic model of hepatocellular carcinoma (HCC) using time-dependent covariates to re-evaluate the prognosis at any stage of the disease. The subjects were consecutive HCC patients who were treated at our institute between 1995 and 2007. We constructed time-fixed and time-dependent prognostic models with a training group (n=336) and compared the prognostic abilities between conventional Cancer of the Liver Italian Program (CLIP) scores, Japan Integrated Staging (JIS) scores, an Okuda classification, and our prognostic models in the testing group (n=227) with the c-index. The time-dependent prognostic model consisted of main tumor size, tumor number, portal vein invasion, distant metastasis, alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), bilirubin, and albumin and the weighted scores were set for each factor depending on the hazard ratio for the prognosis. The prognostic index was determined by summing the scores. The c-index values for the CLIP scores, JIS scores, Okuda classification, and our time-dependent model were 0.741, 0.727, 0.609, and 0.870, respectively. These results indicate that our time-dependent model can estimate the prognosis of HCC more precisely than traditional time-fixed models and can be used to re-predict the prognosis of HCC.

Loss of runt-related transcription factor 3 expression leads hepatocellular carcinoma cells to escape apoptosis.

BACKGROUND: Runt-related transcription factor 3 (RUNX3) is known as a tumor suppressor gene for gastric cancer and other cancers, this gene may be involved in the development of hepatocellular carcinoma (HCC). METHODS: RUNX3 expression was analyzed by immunoblot and immunohistochemistry in HCC cells and tissues, respectively. Hep3B cells, lacking endogenous RUNX3, were introduced with RUNX3 constructs. Cell proliferation was measured using the MTT assay and apoptosis was evaluated using DAPI staining. Apoptosis signaling was assessed by immunoblot analysis. RESULTS: RUNX3 protein expression was frequently inactivated in the HCC cell lines (91%) and tissues (90%). RUNX3 expression inhibited 90±8% of cell growth at 72 h in serum starved Hep3B cells. Forty-eight hour serum starvation-induced apoptosis and the percentage of apoptotic cells reached 31±4% and 4±1% in RUNX3-expressing Hep3B and control cells, respectively. Apoptotic activity was increased by Bim expression and caspase-3 and caspase-9 activation. CONCLUSION: RUNX3 expression enhanced serum starvation-induced apoptosis in HCC cell lines. RUNX3 is deleted or weakly expressed in HCC, which leads to tumorigenesis by escaping apoptosis.

Effect of pegylated interferon therapy on intrahepatic recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND: We wished to determine whether pegylated interferon (PEG-IFN) therapy after curative treatment of hepatocellular carcinoma (HCC) prevents a recurrence of HCC. METHODS: Thirty-seven HCC patients with hepatitis C virus (HCV) infection who were treated with PEG-IFN after curative treatment (PEG-IFN group) and 145 controls without IFN therapy (non-IFN group) were enrolled. The overall survival and recurrence-free survival rates were compared between the groups, and the predisposing factors for recurrence and survival were analyzed. The rates were also examined by propensity score (PS) matched analysis that could minimize selection biases. RESULTS: The median follow-up period was 3.7 years. The 5-year survival rate in the PEG-IFN group (91%) was significantly higher than that in the non-IFN group (56%; P < 0.01). The rate of the second recurrence but not that of the first recurrence of HCC in the sustained virological responder (SVR) group was lower than that in the non-IFN group (P = 0.03). Improvement of survival by PEG-IFN and low rate of second recurrence in the SVR group were also observed in PS matched analysis. Multivariate analysis revealed that PEG-IFN therapy and high serum albumin were good prognostic factors for survival. Although low serum albumin and large and multiple tumors were risk factors for the first recurrence, non-SVR and low serum albumin were risk factors for the second recurrence. CONCLUSION: PEG-IFN-therapy after curative treatment of HCC improved the rate of survival, and SVR was found to be closely correlated with the prevention of recurrence.