Effect of vitamin K2 on the recurrence of hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double-blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC-specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease-free survival (DFS), and the secondary aim was to evaluate dose-response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45-mg/day group, and 185 in the 90-mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843-1.570, one-sided; P=0.811) between the placebo and combined active-drug groups, and the study was discontinued in March 2007. CONCLUSION: Efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed in this double-blind, randomized, placebo-controlled study.

Endoscopic submucosal dissection is an effective and safe therapy for early gastric neoplasms: a multicenter feasible study.

BACKGROUND AND AIM: The technique of endoscopic submucosal dissection (ESD) was introduced to obtain en bloc specimens of large early gastrointestinal neoplasms. The drawback of ESD is its technical difficulty and, consequently, its higher rate of complication. In this multicenter study, we investigated the therapeutic outcomes of ESD in consecutive patients. METHODS: From January 2002 to December 2008, 485 early gastric neoplasms in 418 patients were consecutively treated by using ESD procedure performed by 6 endoscopists in 4 institutions in Tokyo. Demorgraphics, tumor location, therapeutic outcomes, and complication rates were analyzed. RESULTS: The rates of en bloc resection, complete en bloc resection, submucosal invasion, and piecemeal resection were 93.6%, 85.4%, 10.9%, and 5.4%, respectively. In multivariate analysis, the en bloc resection rate was independently lower in lesions in upper portion than in lower portion (P<0.01), lower in larger lesions (>30 mm, P<0.05; 20 to 30 mm, P<0.05), and lower in lesions with a scar (P<0.01). Delayed bleeding occurrence was independently high in larger lesions (>30 mm, P<0.01; 20 to 29 mm, P<0.01) than in small lesions (<20 mm). Institution and endoscopists were not risk factors of en bloc resection and complications CONCLUSIONS: ESD is an effective and safe therapy in the management of early gastric neoplasms when performed by well-trained endoscopists. Endoscopists should recognize the difficulty to perform ESD for en bloc resection of upper lesion, and the risk of delayed bleeding in cases of lesions >2 cm in size.

Identification of a suppressive mechanism for Hedgehog signaling through a novel interaction of Gli with 14-3-3.

Gli transcription factors are central effectors of Hedgehog signaling in development and tumorigenesis. Using a tandem affinity purification (TAP) strategy and mass spectrometry, we have found that Gli1 interacts with 14-3-3epsilon, and that Gli2 and Gli3 also bind to 14-3-3epsilon through homologous sites. This interaction depends on their phosphorylation, and cAMP-dependent protein kinase (PKA), a known negative regulator of Hedgehog signaling serves as a responsible kinase. A Gli2 mutant engineered to eliminate this interaction exhibited increased transcriptional activity (2 approximately 3x). Transcriptional repression by 14-3-3 binding was also observed with Gli3, when its N-terminal repressor domain was deleted. The phosphorylation sites responsible for the binding to 14-3-3 are distinct from those required for proteolysis, the known mechanism for PKA-induced repression of Hh signaling. Our data propose a novel mechanism in which PKA down-regulates Hedgehog signaling by promoting the interaction between Gli and 14-3-3 as well as proteolysis. Given the certain neuronal or malignant disorders in human caused by the abnormality of 17p13 encompassing 14-3-3epsilon overlap with increased Hh signaling, the Gli-14-3-3 interaction may have pathological significance for those human diseases.

Single-balloon versus double-balloon endoscopy for achieving total enteroscopy: a randomized, controlled trial.

BACKGROUND: Balloon endoscopy has been accepted as an effective tool for examining the small intestine. Two types of balloon endoscopy, single and double, are commercially available. The difference in performance between these 2 types of balloon endoscopy has not yet been elucidated. OBJECTIVE: To compare the yield of single-balloon endoscopy (SBE) and double-balloon endoscopy (DBE). DESIGN: Single-center, randomized, controlled trial. SETTING: University hospital in Tokyo, Japan. PATIENTS: Patients with suspected small-bowel disease. INTERVENTIONS: SBE and DBE. MAIN OUTCOME MEASUREMENTS: Outcomes were the total enteroscopy rate, diagnostic yield, complication rate, and clinical outcomes. Analysis was done by intent to treat. RESULTS: The study started in April 2008 and was terminated in April 2010 because of an obvious disadvantage for the SBE group. Thirty-eight patients were enrolled in the study; 18 patients were assigned to the SBE group and 20 to the DBE group. The total enteroscopy rate was 0% in the SBE group and 57.1% in the DBE group (P = .002). In terms of complications, the DBE group had 1 patient with Mallory-Weiss syndrome, and the SBE group had 1 patient with hyperamylasemia. There was no difference in the overall diagnosis rate between the SBE and DBE groups (61.1% vs 50.0%, P = .49). There was no difference in therapeutic outcome between the SBE and DBE groups (27.8% vs 35.0%, P = .63). LIMITATIONS: Relatively small number of study patients. CONCLUSIONS: Total enteroscopy is more easily performed with DBE than with SBE.

New method of covered wallstents for distal malignant biliary obstruction to reduce early stent-related complications based on characteristics.

AIM: We previously reported a low occlusion rate with covered Wallstents for malignant biliary obstruction, but stent-related complications other than occlusion posed a problem. A modified covered Wallstent insertion method based on stent characteristics was evaluated to reduce stent-related complications. METHODS: A total of 138 patients with distal malignant biliary obstruction received covered Wallstent placement. From October 2001 to October 2003, 69 patients received covered Wallstent placement (Group 1). Thereafter, we modified our stent insertion method and 69 patients received stent placement using this modified method from November 2003 to January 2007 (Group 2). The modified insertion method consists of endoscopic sphincterotomy carried out in patients without pancreatic duct invasion and longer stent placement with the center of the stent located in the center of the biliary stricture to prevent pancreatitis, kinking of the bile duct, and stent dislocation. A comparative analysis was carried out using prospectively collected data in these two cohorts. RESULTS: Tumor ingrowth was not observed, and stent occlusion rate was 18.8% in Group 1 and 23.2% in Group 2. The overall rates of stent-related complications did not differ (39.1% in Group 1 and 30.4% in Group 2), but stent-related complications within 3months decreased from 22 episodes in Group 1 to 13 episodes in Group 2. Median event-free survival was prolonged by modified stent insertion method (125days in Group 1 and 268days in Group 2, P=0.020), although cumulative survival and stent patency were not significantly different. CONCLUSIONS: Our modified method of covered Wallstent placement showed improved event-free survival.

Surveillance of small intestinal abnormalities in patients with hepatocellular carcinoma: a prospective capsule endoscopy study.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) sometimes suffer from obscure gastrointestinal bleeding. Portal hypertension (PH), common in cirrhosis, induces esophagogastric varices. Because of the location, PH also may influence mucosal abnormalities in the small intestine. The objective of this study is to estimate the prevalence of small intestinal mucosal abnormalities in HCC patients using capsule endoscopy (CE). PATIENTS AND METHODS: We prospectively conducted CE in HCC patients, and analyzed the findings in relation to hepatic function, the number and size of HCC tumor and findings obtained by conventional endoscopy. RESULTS: Thirty-six patients (aged 66.7 ± 7.5 years, 29 men) underwent CE. Abnormal findings in the small bowel were found in 16 patients (44%), angioectasias in eight patients (22%), erosions in five (14%), varices in four (11%), polyps in four (11%), and submucosal tumor in one (3%). The patients with angioectasia had a larger spleen index than the no abnormal lesions group (85.4 ± 15.8 vs 59.0 ± 24.4, P = 0.02). The former group had been more frequently treated for esophageal varices endoscopically (62% vs 15%, P = 0.02). Large HCC nodules seemed more common in the patients with angioectasia than subjects without abnormal lesions (38% vs 5%, P = 0.06). Small intestinal varices also seemed to have a positive association with large HCC. During the follow up after CE, one patient with small intestinal polyps suffered from obscure gastrointestinal bleeding. CONCLUSIONS: CE revealed that HCC patients frequently have small intestinal mucosal lesions. In particular, small intestinal angioectasia, which may cause obscure gastrointestinal bleeding, seems to be associated with portal hypertension.

Macroscopic morphologic subtypes of laterally spreading colorectal tumors showing distinct molecular alterations.

Recent advances in colonoscopic techniques have resulted in more frequent detection of superficial-type colorectal tumors, that is, laterally spreading tumors (LSTs), although little is known about the characteristic clinical features and genetic alterations of LSTs. To elucidate the molecular characteristics of LSTs, genetic alterations in the KRAS, BRAF and PIK3CA genes and abnormal expression of the p53, beta-catenin and MYC proteins were analyzed using direct DNA sequencing and immunohistochemistry for 50 protruded-type tumors (Protruded), 35 granular-type LSTs (LST-G) and 19 nongranular-type LSTs (LST-NG). In addition, loss of heterozygosity (LOH) close to the adenomatous polyposis coli (APC) gene (5q21) was examined in these tumors. In univariate analyses, significant differences were noted in the percentages with KRAS mutations (Protruded, LST-G, LST-NG = 30.0%, 54.3%, 21.1%, respectively, p = 0.0156), nuclear accumulation of beta-catenin (Protruded, LST-G, LST-NG = 50.0%, 37.1%, 68.4%, respectively, p = 0.0267), expression of MYC (Protruded, LST-G, LST-NG = 26.0%, 17.1%, 42.1%, respectively, p = 0.0456) and LOH at the APC gene locus (Protruded, LST-G, LST-NG = 22.0%, 20.0%, 47.4%, respectively, p = 0.0302). Multivariate analysis demonstrated that the macroscopic subtype of LST was significantly associated with KRAS mutation (for LST-NG: odds ratio [OR] 0.23, 95% CI 0.06-0.90) and nuclear accumulation of beta-catenin (for LST-NG: OR 4.05, 95% CI 1.11-14.8). Our data revealed that the 2 subtypes of LST have different molecular characteristics, suggesting that 2 or more different molecular mechanisms result in colorectal tumors with a similar growth pattern.

Decreased expression of the RAS-GTPase activating protein RASAL1 is associated with colorectal tumor progression.

BACKGROUND & AIMS: Although colorectal cancer (CRC) progression has been associated with alterations in KRAS and RAS signaling, not all CRC cells have KRAS gene mutations. RAS activity is modulated by RAS-GTPase-activating proteins (RASGAPs), so we investigated the role of RASGAPs in CRC progression. METHODS: The level of RASGAP expression in CRC cells was analyzed using quantitative real-time polymerase chain reaction. The expression of the RAS protein activator like-1 (RASAL1) was examined in clinical colorectal neoplasms using immunohistochemistry. The clinicopathologic (age, sex, and tumor site and grade) and molecular (KRAS gene mutation, as well as CTNNB1 and TP53 expression patterns) factors that could affect RASAL1 expression were examined. RESULTS: Of 12 RASGAPs examined, expression levels of only RASAL1 decreased in CRC cells; RASAL1 expression decreased in most CRC cells with wild-type KRAS gene but rarely in those with mutant KRAS gene. A transfection assay showed that RASAL1 repressed RAS/mitogen-activated protein kinase signaling in response to growth factor stimulation and reduced proliferation of CRC cells that contained wild-type KRAS gene. RASAL1 expression was detected in 46.9% (30/64) of adenocarcinoma, 17.4% (8/46) of large adenoma, and no (0/42) small adenoma samples. RASAL1 expression levels were correlated with the presence of wild-type KRAS gene in CRC tumor samples (P= .0010), distal location (P= .0066), and abnormal expression of TP53 (P= .0208). CONCLUSIONS: RASAL1 expression is reduced in CRC cells that contain wild-type KRAS gene. Reductions in RASAL1 expression were detected more frequently in advanced lesions than in small adenomas, suggesting that RASAL1 functions in the progression of benign colonic neoplasms.

Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography.

UNLABELLED: Liver stiffness, noninvasively measured by transient elastography, correlates well with liver fibrosis stage. The aim of this prospective study was to evaluate the liver stiffness measurement (LSM) as a predictor of hepatocellular carcinoma (HCC) development among patients with chronic hepatitis C. Between December 2004 and June 2005, a total of 984 HCV-RNA positive patients, without HCC or a past history of it, visited the University of Tokyo Hospital. LSM was performed successfully in 866 patients, who gave informed consent. During the follow-up period (mean, 3.0 years), HCC developed in 77 patients (2.9% per 1 person-year). The cumulative incidence rates of HCC at 1, 2, and 3 years were 2.4%, 6.0%, and 8.9%, respectively. Adjusting for other significant factors for HCC development, patients with higher LSM were revealed to be at a significantly higher risk, with a hazard ratio, as compared to LSM < or =10 kPa, of 16.7 (95% confidence interval [CI], 3.71-75.2; P < 0.001) when LSM 10.1-15 kPa, 20.9 (95% CI, 4.43-98.8; P < 0.001) when LSM 15.1-20 kPa, 25.6 (95%CI, 5.21-126.1; P < 0.001) when LSM 20.1-25 kPa, and 45.5 (95% CI, 9.75-212.3; P < 0.001) when LSM >25 kPa. CONCLUSIONS: This prospective study has shown the association between LSM and the risk of HCC development in patients with hepatitis C. The utility of LSM is not limited to a surrogate for liver biopsy but can be applied as an indicator of the wide range of the risk of HCC development.

Endoscopic evaluation of factors contributing to intrapancreatic biliary stricture in autoimmune pancreatitis.

BACKGROUND: Intrapancreatic bile duct stricture in autoimmune pancreatitis (AIP) is usually diagnosed as sclerosing cholangitis even if the stricture is limited to the intrapancreatic area. However, it is not known whether compression caused by pancreatic edema or biliary wall thickening causes such a biliary stricture. OBJECTIVE: Our purpose was to clarify the factor that contributes to intrapancreatic biliary stricture in AIP: pancreatic head lesion or biliary wall thickening. DESIGN: Single-center retrospective study. SETTING: This study was performed in a tertiary care academic medical center. PATIENTS: Fifty-six patients with AIP were included. MAIN OUTCOME MEASUREMENTS: The relationship between the presence of a pancreatic head lesion and intrapancreatic biliary stricture was examined. In addition, the relationship between the extent of the intrapancreatic biliary stricture and the wall thickening was evaluated. RESULTS: Among 44 patients with a pancreatic head lesion, 41 (93%) had intrapancreatic bile duct stricture. Among 12 patients without a pancreatic head lesion, only 2 had such a stricture (P < .0001). Intraductal US showed average intrapancreatic biliary wall thickening with severe stricture of 2.7 +/- 1.0 mm, significantly thicker than that with mild stricture (1.9 +/- 0.35 mm; P = .0200). LIMITATIONS: Intraductal US was not performed in all patients. CONCLUSIONS: Both pancreatic edema and biliary wall thickening influenced intrapancreatic biliary stricture in AIP. This type of stricture should be differentiated from extrapancreatic biliary stricture that may be caused by biliary wall thickening only.

Double-stranded RNA-activated protein kinase inhibits hepatitis C virus replication but may be not essential in interferon treatment.

BACKGROUND: Double-stranded RNA-activated protein kinase (PKR), an interferon (IFN)-stimulated gene, is activated by binding with double-stranded RNA, a putative replicative intermediate of the hepatitis C virus (HCV). Activated PKR phosphorylates the alpha subunit of eukaryotic initiation factor-2 to inhibit the translation of viral protein. AIMS/METHODS: We established stable PKR knockdown Huh7 cells using RNA interference and investigated the effect of PKR against HCV replication using a subgenomic replicon that expressed luciferase reporter protein and the JFH1 full-length HCV genome. RESULTS: In stable PKR knockdown cells that harboured a subgenomic replicon, luciferase activity was approximately three times higher than that of control cells, indicating that the subgenomic replicon replicated with a higher efficiency in stable PKR knockdown cells than that in control cells. Furthermore, stable PKR knockdown cells secreted significantly more HCV particles than did control cells after transfection with the full-length HCV genome. The replication of the subgenomic replicon was suppressed by the addition of IFN-alpha in both cells. Although the extent of suppression was significantly lower in stable PKR knockdown than control cells using a low concentration (2.5-5 U/ml) of IFN-alpha, even 10 U/ml IFN-alpha suppressed the replication of subgenomic replicon by >98% in both cells. CONCLUSIONS: Double-stranded RNA-activated protein kinase plays an important role in suppressing HCV replication in an innate state, but may not be essential in IFN therapy.

Management of distal malignant biliary obstruction with the ComVi stent, a new covered metallic stent.

BACKGROUND: The covered metallic stent is effective for managing malignant distal biliary obstructions. The most popular covered metallic stent is the covered Wallstent (CWS). This study estimated the efficacy and safety of a new expanded polytetrafluoroethylene (e-PTFE)-covered nitinol metallic stent, the ComVi stent. This covered metallic stent consists of an e-PTFE membrane sandwiched between two uncovered metallic stents with weak axial (straightening) force. Wire is exposed on both the inner and outer surfaces. METHODS: Between May 2005 and April 2007, ComVi stents were placed consecutively in 47 patients with unresectable malignant distal biliary obstruction. The cases involved 35 pancreatic cancers, 8 metastatic nodes, 2 gallbladder cancers, and 2 bile duct cancers. The patients were compared with 47 patients who received CWS placement between August 2001 and May 2005 matched for age, sex, and causative disease from 133 cases. RESULTS: No significant differences in stent patency or patient survival were found. Stent occlusion was observed in 13 patients (27.7%) in the ComVi group and 10 patients (21.3%) in the CWS group. The cause of occlusion in both groups was tumor overgrowth (4.25% vs 4.2%), sludge (8.5% vs 6.3%), impaction of food scraps (14.9% vs 2.1%), and bile duct kinking (0% vs 8.4%). Other complications were migration (2.1% vs 17.0%; p = 0.0304) and cholecystitis (2.1% vs 6.3%), and there were significant differences in the incidence of complications except for occlusion (4.2% vs 24.6%; p = 0.0142). CONCLUSION: The ComVi stent has a patency similar to that of the CWS and a lower incidence of migration. However, early occlusion by food impaction was increased and should be resolved.

Endoscopic management of biliocutaneous fistula after percutaneous radiofrequency ablation therapy for hepatocellular carcinoma.

Our patient was a 70-year-old man with hepatocellular carcinoma (HCC) and liver cirrhosis (Child-Pugh B). He had a history of distal gastrectomy with Billroth II reconstruction for duodenal ulcer and hepatectomy for HCC. One month after percutaneous radiofrequency ablation (RFA) for recurrent HCC, biliocutaneous fistula was observed. The cholangiogram demonstrated leakage of contrast material from an intrahepatic duct into the fistula, and a nasobiliary catheter was placed. Subsequently, the discharge of bile steadily decreased and stopped. Follow-up cholangiogram revealed no evidence of bile leakage. Biliocutaneous fistula is an extremely rare complication after percutaneous RFA, and the present case report suggests that endoscopic drainage is the first-line therapy for bile leaks after RFA.

Experiences of biliary interventions using short double-balloon enteroscopy in patients with Roux-en-Y anastomosis or hepaticojejunostomy.

BACKGROUND: The efficacy of double-balloon enteroscopy (DBE) for biliary interventions has been shown in patients with surgical anatomy. However, the use of available endoscopic retrograde cholangiography accessories during this procedure is limited because of the length of the conventional instrument (200 cm). The aim of this study was to evaluate the feasibility of short DBE for managing biliary disorders in patients with a Roux-en-Y gastrectomy or hepaticojejunostomy (HJ). PATIENTS AND METHODS: Using a short enteroscope (152 cm) and commercially available endoscopic retrograde cholangiography accessories, biliary interventions were performed in six patients with Roux-en-Y reconstruction or HJ anastomosis. RESULTS: A total of 12 biliary interventions were performed; balloon dilations of the HJ anastomosis or intrahepatic ducts (four patients), nasobiliary drainages (three patients), bile duct stone removal after endoscopic papillary large balloon dilation with or without small sphincterotomy (two patients), and a biliary stent placement (one patient). One patient showed retroperitoneal air following endoscopic papillary large balloon dilation, but recovered conservatively. CONCLUSIONS: Biliary interventions via DBE using a short enteroscope are feasible in patients with surgical anatomy.

Regulation of the hedgehog signaling by the mitogen-activated protein kinase cascade in gastric cancer.

The hedgehog and mitogen-activated protein kinase (MAPK) signaling pathways regulate growth in many tumors, suggesting cooperation between these two pathways in the regulation of cell proliferation. However, interactions between these pathways have not been extensively studied. We assessed cross-talk between hedgehog and MAPK signaling in the regulation of cell proliferation in gastric cancer. We showed that PTCH expression was significantly correlated with extracellular signal-regulated kinase (ERK) 1/2 phosphorylation (P = 0.016) as well as SHH expression (P = 0.034) in the 35 gastric cancers assessed by immunohistochemistry. Indeed, MAPK signaling increased the GLI transcriptional activity and induced the expression of hedgehog target genes in gastric cancer cells. The inductive effect of activated KRAS and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1 was blocked by the suppressor of fused (SUFU), indicating that MAPK signaling regulates GLI activity via a SUFU-independent process. Moreover, the deletion of the NH2-terminal domain of GLI1 gene resulted in reduced response to MEK1 stimulation. Our results suggest that the KRAS-MEK-ERK cascade has a positive regulatory role in GLI transcriptional activity in gastric cancer.

Potential contribution of tumor suppressor p53 in the host defense against hepatitis C virus.

UNLABELLED: Infection by hepatitis C virus (HCV) usually results into chronic hepatitis that can ultimately lead to cirrhosis and hepatocellular carcinoma. Type 1 interferons (IFN-alpha/beta) constitute the primary cellular defense against viral infection including HCV. IFN binding to their receptors activates associated Jak1 and Tyk2 kinases, which ultimately leads to phosphorylation and assembly of a signal transducer and activator of transcription protein (STAT)1-STAT2-interferon regulatory factor (IRF)9 trimetric complex called interferon-stimulated gene factor 3 that translocates into the nucleus and binds to the interferon- stimulated response elements (ISRE), leading to transcriptional induction of several antiviral genes, including double-stranded RNA-activated protein kinase (PKR), 2',5'- oligoadenylate synthetase (OAS), and myxovirus resistance protein A (MxA). Understanding the mechanisms of how the virus evades this cellular innate defense and establishes a chronic infection is the key for the development of better therapeutics against HCV infection. Here, we demonstrate that p53 could have a crucial role in the cellular innate defense against HCV. We observed significantly higher levels of HCV RNA replication and viral protein expression in the Huh7 cells when their p53 expressions were knocked down. Moreover, IFN treatment was less effective in inhibiting the HCV RNA replication in the p53-knocked-down (p53kd) Huh7 cells. In fact, the activation of the ISRE and the induction of ISGs were significantly attenuated in the p53kd Huh7 cells and p53 was found to directly interact with IRF9. CONCLUSION: These observations underscore the potential contributions of the tumor suppressor p53 in cellular antiviral immunity against HCV with possible therapeutic implications.

S-1 monotherapy in patients with advanced biliary tract cancer.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of single-agent S-1 in patients with advanced biliary tract cancer. METHODS: S-1 was administered orally at a dose of 80 mg/m2 for 28 days, followed by 14 days of rest (1 cycle); treatment was repeated until disease progression, unacceptable toxicity, or patient refusal. RESULTS: Forty-five patients were enrolled between January 2005 and June 2008. Among these, 29 patients received S-1 as first-line chemotherapy and 16 patients received S-1 as second-line chemotherapy. The response rates for first- and second-line chemotherapy were 17.2 and 18.8%, respectively. The median times to progression for the first- and second-line chemotherapy groups were 4.2 and 5.5 months (p = 0.91), respectively. The median overall survival and 1-year survival rate for each group were 8.7 and 8.0 months and 42.2 and 38.2%, respectively (p = 0.62). Only the first-line chemotherapy group experienced grade 3/4 toxicities, including leukopenia (6.9%), neutropenia (10.3%), anemia (6.9%), thrombocytopenia (10.3%) and total bilirubin elevation (3.4%). CONCLUSION: S-1 monotherapy is a feasible and moderately efficacious treatment for advanced biliary tract cancer, as a first- or second-line chemotherapy regimen.

A pilot study for combination chemotherapy using gemcitabine and S-1 for advanced pancreatic cancer.

OBJECTIVES: We performed a pilot study of a modified combination chemotherapy regimen with S-1 plus gemcitabine for patients with advanced pancreatic cancer. METHODS: Gemcitabine was administered at a dose of 1,000 mg/m(2) in a 30-min intravenous injection on days 1 and 15. S-1 was administered orally at a dose of 40 mg/m(2) twice daily for 14 consecutive days followed by a 14-day rest. Each cycle was repeated every 28 days. RESULTS: Sixteen patients were enrolled. No complete response was observed and partial response was observed in 5 patients (31.3%), stable disease in 10 patients (62.5%) and progressive disease in 1 patient (6.3%). The median time to progression was 10.0 months (95% CI 4.4-N.A.) and the median survival time was 20.4 months (95% CI 8.6-24.1 months). The major toxicities were grade 3 neutropenia (25.0%) and grade 3 anemia (6.3%). There were no grade 4 toxicities. CONCLUSIONS: Combination therapy with gemcitabine and S-1 using the modified 4-week schedule was well tolerated and efficacious for advanced pancreatic cancer.

Measurement of radial and axial forces of biliary self-expandable metallic stents.

BACKGROUND: Efforts to understand the properties of self-expandable metallic stents (SEMSs) through their mechanical properties have progressed. Among them, radial force (RF) is well known as an expanding force, but axial force (AF) has not been measured before. Correlations of these properties to clinical results are not well known. OBJECTIVE: We measured RF and AF of 14 different SEMSs and discussed the results in terms of clinical implications. DESIGN: Experimental study. SUBJECTS: Measurement of RF and AF of 14 different covered and uncovered SEMSs. METHODS: RF was measured with an RF measurement machine manufactured by Machine Solution, and AF was measured with in-house equipment. RESULTS: Measurements of RF in the process of expansion showed characteristic patterns closely related to the structures and materials of SEMSs. Results of AF measurement can be classified into 3 groups: high, medium, and low AF, depending on the type of SEMS. AF decreased with an increase of the length of stents. A plot of RF against AF revealed 3 distinguished RF/AF combinations and indicated the importance of understanding the properties by not only RF or AF individually but also by RF/AF combination. LIMITATIONS: In vitro study using measurement equipment. CONCLUSION: It was demonstrated that a combination of RF and AF is more effective than RF or AF individually in understanding the clinical implications of SEMSs. More work is needed to correlate mechanical properties with clinical results by designing model experiments.

Polymorphism of OAS-1 determines liver fibrosis progression in hepatitis C by reduced ability to inhibit viral replication.

BACKGROUND: Progression of disease after hepatitis C virus (HCV) infection differs among individuals, indicating a possibility of participation of host genetic factors. 2'-5'-oligoadenylate synthetase 1 (OAS-1), an important component of the innate immune system, has an antiviral function, and may therefore have a certain relationship with progression of disease. AIM: To evaluate single nucleotide polymorphisms (SNPs) of OAS-1 and its relationship with the disease status of HCV infection. METHODS: Six SNPs of OAS-1 were selected and examined in 409 Japanese patients with chronic HCV infection using the TaqMan PCR genotyping method. The relationship of SNP genotypes and clinical manifestations of patients was analysed. Then, a pair of OAS-1-expression plasmids mimicking the clinical-related SNPs were created and transfected into liver cells carrying the HCV subgenomic replicon or the full-length genome, JFH1, and HCV replication after transfection was compared. RESULTS: Patients with genotypes A/A, A/G and G/G of an SNP of OAS-1 at the exon 3 of its coding sequence were at gradient increased risks of suffering from higher serum alanine aminotransferase (P<0.001) and aspartate aminotransferase (P=0.001), higher degree of liver fibrosis (P=0.010) and higher presence of liver cirrhosis (P=0.001). By multivariate logistic regression analysis, genotype G/G was an independent factor associated with cirrhosis (P=0.013, odds ratio 3.11, 95% confidence interval 1.27-7.63). In liver cells, OAS-1 with the G allele showed lower ability to inhibit virus replication than OAS-1 with the A allele (P=0.004). CONCLUSIONS: The SNP of OAS-1 at the exon 3 of its coding sequence was associated with progression of disease in Japanese patients with HCV infection.