Kenji Kuwaki

Diagnostic accuracy of narrow-band imaging and pit pattern analysis significantly improved for less-experienced endoscopists after an expanded training program

BACKGROUND Previous reports assessing diagnostic skill using narrow-band imaging (NBI) and pit pattern analysis for colorectal polyps involved only highly experienced endoscopists. OBJECTIVE To evaluate diagnostic skills of less-experienced endoscopists (LEE group) for differentiation of diminutive colorectal polyps by using NBI and pit pattern analysis with and without magnification after an expanded training program. DESIGN Prospective study. PATIENTS This study involved 32 patients with 44 colorectal polyps (27 adenomas and 17 hyperplastic polyps) of < or =5 mm that were identified and analyzed by using conventional colonoscopy as well as non-magnification and magnification NBI and chromoendoscopy followed by endoscopic removal for histopathological analysis. INTERVENTION Before a training course, 220 endoscopic images were distributed in randomized order to residents with no prior endoscopy experience (NEE group) and to the LEE group, who had performed colonoscopies for more than 5 years but had never used NBI. The 220 images were also distributed to highly experienced endoscopists (HEE group) who had routinely used NBI for more than 5 years. The images were distributed to the NEE and LEE groups again after a training class. Magnification NBI and chromoendoscopy images were assessed by using the Sano and Kudo classification systems, respectively. MAIN OUTCOME MEASUREMENTS Diagnostic accuracy and interobserver agreement for each endoscopic modality in each group. RESULTS Diagnostic accuracy was significantly higher, and kappa (kappa) values improved in the LEE group for NBI with high magnification after expanded training. Diagnostic accuracy and kappa values when using high-magnification NBI were highest among endoscopic techniques for the LEE group after such training and the HEE group (accuracy 90% vs 93%; kappa = 0.79 vs 0.85, respectively). LIMITATIONS Study involved only polyps of < or =5 mm. CONCLUSION Using high-magnification NBI increased the differential diagnostic skill of the LEE group after expanded training so that it was equivalent to that of the HEE group.

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.

Effect of hepatic arterial infusion chemotherapy of 5-fluorouracil and cisplatin for advanced hepatocellular carcinoma in the Nationwide Survey of Primary Liver Cancer in Japan

Background:The efficacy of hepatic arterial infusion chemotherapy for the treatment of advanced hepatocellular carcinoma (HCC) remains unclear.Methods:The outcome of 476 patients with HCC who underwent hepatic arterial infusion chemotherapy with 5-fluorouracil and cisplatin (HAIC) were compared with 1466 patients who did not receive active therapy.Results:A survival benefit of the therapy after adjusting for known risk factors was observed (hazard ratio, 0.48; 95% CI, 0.41–0.56; P<0.0001). In propensity score-matched analysis (n=682), median survival time was longer for patients who underwent chemotherapy (14.0 months) than for patients who did not receive active treatment (5.2 months, P<0.0001).Conclusion:For advanced HCC, HAIC is considered to be an effective treatment.

Prognostic factors and treatment effects for hepatocellular carcinoma in Child C cirrhosis

The aim of this study is to elucidate the prognostic factors and the treatment effect on survival in hepatocellular carcinoma (HCC) patients with Child C cirrhosis. Out of 3330 newly discovered HCC patients, 157 consecutive HCC individuals with Child C cirrhosis were enrolled. The prognostic factors were examined by Cox proportional hazards regression analysis and their survival was compared by propensity score-matched analysis. Multivariate analysis revealed that high serum bilirubin (>3 mg dl−1), the presence of uncontrollable ascites, and a high platelet count (>8 × 104 mm−3), so-called background liver factors, as well as multiple tumours, large tumours (>3 cm), high alpha-fetoprotein (>400 ng ml−1), and the presence of portal vein thrombus, so-called tumour factors, were factors of poor prognosis. While transcatheter arterial chemoembolisation (TACE) was a factor of good prognosis (relative risk=0.50, 95%CI=0.27–0.89, P=0.019), local ablation therapy and transcatheter arterial chemoinfusion (TAI) were not significant prognostic factors. The survival of patients who received TACE was superior to matched patients without active treatment (P=0.009); however, we did not observe survival benefit after local ablation therapy or TAI. These results suggested that tumour factors as well as background liver factors are prognostic factors of HCC even in patients with Child C cirrhosis, and selective use of TACE in these patients provides survival benefit.

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.

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.

Age-related methylation in normal colon mucosa differs between the proximal and distal colon in patients who underwent colonoscopy

OBJECTIVES To examine the difference in the methylation status in normal colon mucosa between the proximal and distal colon, in relation to the correlation between the methylation status of normal mucosa and characteristics of neoplasia. DESIGN AND METHODS Paired biopsy specimens of normal mucosa from the proximal and distal colon of 82 patients who underwent colonoscopy were obtained. The methylation status of the promoter region of estrogen receptor 1 (ESR1) and myogenic differentiation 1 (MYOD1) was examined. RESULTS Normal mucosa was more highly methylated in the distal than in the proximal colon in both ESR1 and MYOD1 loci (p<0.0001 and p=0.0009, respectively). Advanced characteristics of polyps in the distal colon were frequently observed in patients with lower methylation of ESR1 in the distal colon normal mucosa. CONCLUSIONS Methylation levels in normal mucosa differ between the proximal and distal colon, and lower methylation of ESR1 in the distal colon normal mucosa may correlate with advanced features of neoplasia in the distal colon.

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

BackgroundRunt-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).MethodsRUNX3 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.ResultsRUNX3 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.ConclusionRUNX3 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.

Evolution of prognostic factors in hepatocellular carcinoma in Japan

Aliment Pharmacol Ther 31, 407–414

Involvement of platelets in extrahepatic metastasis of hepatocellular carcinoma

Recently, a relationship between platelets and cancer metastasis has been reported. The aim of this study is to elucidate the risk factors for extrahepatic metastasis (EHM), with emphasis on association with platelets in patients, with hepatocellular carcinoma (HCC).