Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial.

BACKGROUND: Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). PATIENTS AND METHODS: We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0 - 1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. RESULTS: Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4 months with GC and 15.1 months with GS, HR, 0.945; 90% confidence interval (CI), 0.78-1.15; P = 0.046 for non-inferiority]. The median PFS was 5.8 months with GC and 6.8 months with GS (HR 0.86; 95% CI 0.70-1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. CONCLUSIONS: GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. CLINICAL TRIAL NUMBER: This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.

Peroral video cholangioscopy to evaluate indeterminate bile duct lesions and preoperative mucosal cancerous extension: a prospective multicenter study.

BACKGROUND AND STUDY AIMS: Despite the development of peroral video cholangioscopy (PVCS), no prospective multicenter studies have been undertaken to investigate the diagnostic accuracy of PVCS in biliary tract diseases. Therefore, the aim of this study was to clarify the accuracy of PVCS in evaluating biliary tract lesions. PATIENTS AND METHODS: This study was a prospective multicenter study at five tertiary referral centers in Japan and included 87 eligible patients with biliary tract diseases who underwent PVCS. The study evaluated the ability of PVCS to diagnose indeterminate biliary tract diseases, detect mucosal cancerous extension preoperatively in extrahepatic bile duct cancers, and predict adverse events. RESULTS: The use of PVCS appearance alone correctly distinguished benign from malignant indeterminate biliary lesions in 92.1 % of patients whereas biopsy alone was accurate in 85.7 %. In extrahepatic bile duct cancer, mucosal cancer extended histologically at least 20 mm in 34.7 % (17/49) of patients. The accuracy rate of PVCS to evaluate the presence or absence of mucosal cancerous extension by endoscopic retrograde cholangiography (ERC) alone, ERC with PVCS, and ERC with PVCS + biopsy were 73.5 %, 83.7 %, and 92.9 %, respectively. Adverse events were seen in 6.9 % of PVCS patients, but no serious complications were observed. CONCLUSION: PVCS enhanced the accurate diagnosis of biliary tract lesions by providing excellent resolution in combination with biopsy.

Influence of altered occlusal guidance on masticatory muscle activity during clenching.

This study investigated the influence of experimentally altered occlusal guidance on masticatory muscle activity. Twenty healthy human subjects (15 males and five females with an average age of 26.5 years) volunteered to participate in this study. Metallic occlusal overlays were fabricated for the lower working side canine and overlaid on the second molar and the non-working side second molar to simulate a canine-protected occlusion, group function occlusion and bilateral balanced occlusion. Electromyography (EMG) activities in the bilateral masseter, anterior and posterior temporalis were recorded during maximal clenching. The experimental occlusal pattern revealed to have statistically significant effects on EMG activity. As the most characteristic change, EMG activity in the anterior temporalis significantly increased in the simulated group function occlusion and the simulated bilateral balanced occlusion compared with the simulated cuspid protected occlusion. The increased teeth contacts to the posterior region altered the unilateral pattern of the anterior temporalis activity to the bilateral pattern, while that of masseter activity remained unchanged.

The influence of altered occlusal guidance on condylar displacement during submaximal clenching.

As cited in literatures, canine protected occlusion has a potential to reduce clenching induced temporomandibular joint loadings. However, these previous studies did not perform a control of the clenching level which differed with the depending occlusal conditions. This result may be due largely to an associated reduced jaw closing muscle activity. The present study has investigated clenching induced condylar displacements with controlled clenching level. Twenty healthy human subjects (15 males and five females with an average age of 26.5 years) volunteered to participate in this study. Metallic occlusal overlays were fabricated for the lower working side canine and overlaid to the second molar and the non-working side second molar in order to simulate a canine protected occlusion, group function occlusion and bilateral balanced occlusion. Electromyographic (EMG) activity from the bilateral masseter, anterior temporalis, and posterior temporalis was recorded. These signals were rectified, summarized, and presented to each subject using an oscilloscope screen. Using this visual feedback, subjects were asked to perform clenching tasks at a 50% level of maximal voluntary contraction exerted with simulated group function occlusion and three-dimensional condylar displacements were recorded. An experimental occlusal pattern that shows statistically significant affects on condylar displacements (anova: P<0.001) was found. When compared with the simulated canine protected occlusion, the simulated group function occlusion caused smaller working side condylar displacement and the simulated bilateral balanced occlusion caused significantly smaller non-working side and working side condylar displacements. These results suggest that the increased working side tooth contacts have a potential to reduce working side joint loadings, and a balancing side contact has a potential to reduce non-working side joint loadings, under the laboratory condition where the clenching level is controlled.

Chronic intraperitoneal endotoxin treatment in rats induces resistance to d-tubocurarine, but does not produce up-regulation of acetylcholine receptors.

BACKGROUND: Chronic systemic inflammation resulting from intraperitoneal Eschevichia coli endotoxin administration or Corynebacterium injections induces tolerance to non-depolarizing neuromuscular blockers in rodents. Although this has been explained as up-regulation of muscle acetylcholine receptors (AChR), the numbers of involved receptors have not been documented. The aim of this study was to determine the effects of chronic endotoxin administration on rat muscle AChR. METHODS: One day after one, seven, or 14 daily intraperitoneal doses of lipopolysaccharide endotoxin (0 or 0.5 mg kg(-1)), we studied in vivo dose-response relationships for d-tubocurarine (d-Tc) and AChR binding using [125I]alpha-bungarotoxin as a ligand. RESULTS: One day after seven and 14 daily intraperitoneal doses of endotoxin, the effective dose of d-Tc required to suppress the twitch response to 50% of the control (ED50) was significantly increased compared with that of time-matched control rats (146.5 +/- 38.2 vs. 76.1 +/- 9.0 microg kg(-1) for seven doses; 116.4 +/- 51.3 vs. 74.4 +/- 9.6 micro g kg-1 for 14 doses, P < 0.05). However, this was not associated with an increase in the number of AChR in the anterior tibial muscle or diaphragm. CONCLUSIONS: Mechanisms other than AChR up-regulation might be responsible for the increased d-Tc requirement during chronic intraperitoneal endotoxin administration.

The influence of altered occlusal guidance on condylar displacement.

This study investigated mandibular displacement and masticatory muscle activity during clenching in lateral occlusal position in relation to the lateral occlusal pattern. Twenty healthy human subjects (mean = 26.5 years) volunteered for this study. Metallic occlusal overlays were fabricated for the lower working side canine to second molar and non-working side second molar in order to simulate a canine protected occlusion, group function occlusion and bilateral balanced occlusion (balancing contact). Three-dimensional displacements of the bilateral condyle and electromyography (EMG) activities in the bilateral masseter, anterior and posterior temporalis were recorded during maximal clenching. The experimental occlusal pattern was revealed to have statistically significant effects on both condylar displacement and EMG activity (P < 0.001 and P < 0.001, respectively). When compared to the simulated group function occlusion, the simulated canine protected occlusion and balancing contact caused statistically significant smaller superior displacements of the non-working side condyle, which suggests that they may result in reduced temporomandibular joint (TMJ) loading. Furthermore, the simulated canine protected occlusion was associated with the lowest EMG activity, which suggests that this occlusal pattern has the capacity to reduce the level of parafunctional activity.

Disturbances in hepatocellular function during cardiopulmonary bypass using propofol anaesthesia.

BACKGROUND AND OBJECTIVE: Serum hyaluronate is thought to be an indicator of derangement in hepatocellular integrity, and the change in serum hyaluronate is a useful indicator in various liver disorders. We assessed the changes in serum hyaluronate in patients undergoing coronary artery bypass graft surgery. METHODS: Eleven patients scheduled for elective coronary artery bypass graft surgery were studied. An oximetry oxygen saturation catheter was inserted into the right hepatic vein to permit monitoring of hepatic venous oxygen saturation. Perioperative measurements included: haemodynamic variables; systemic oxygen delivery and uptake; arterial, mixed venous and hepatic venous oxygen saturation; arterial and hepatic venous plasma concentrations of lactate, arterial ketone body ratio (ratio of acetoacetate to 3-hydroxybutyrate); and arterial and hepatic venous hyaluronate were measured. RESULTS: Arterial and hepatic venous hyaluronate increased during cardiopulmonary bypass compared with the prebypass period. These increases returned to prebypass values after the cessation of bypass (hepatic venous hyaluronate value at the prebypass period: 26 +/- 13 ng mL(-1), during bypass: 77 +/- 40 ng mL(-1); 1 h after bypass: 57 +/- 42 ng mL(-1); 6 h after bypass: 32 +/- 15 ng L(-1), 24 h after bypass; 62 +/- 21 ng mL(-1); mean +/- SD, P < 0.05). The arterial and hepatic venous hyaluronate during cardiopulmonary bypass was correlated with total bilirubin and hepatic venous lactate concentrations 6 h after bypass (arterial hyaluronate at cardiopulmonary bypass period vs. total bilirubin at 6 h after bypass; r=0.793, P=0.0036, hepatic venous hyaluronate during bypass vs. that at 6 h after bypass; r=0.795, P=0.0035). CONCLUSIONS: Hepatocellular integrity might be disturbed during cardiopulmonary bypass when propofol anaesthesia is used.

Hepatosplanchnic oxygenation is better preserved during mild hypothermic than during normothermic cardiopulmonary bypass.

PURPOSE: To assess and compare the effects of normothermic and mild hypothermic cardiopulmonary bypass (CPB) on hepatosplanchnic oxygenation. METHODS: We studied 14 patients scheduled for elective coronary artery bypass graft surgery who underwent normothermic (>35 degrees C; group I, n=7) or mild hypothermic (32 degrees C; group II, n=7) CPB. After induction of anesthesia, a hepatic venous catheter was inserted into the right hepatic vein to monitor hepatic venous oxygen saturation (ShvO(2)) and hepatosplanchnic blood flow by a constant infusion technique that uses indocyanine green. RESULTS: The ShvO(2) decreased from a baseline value in both groups during CPB and was significantly lower at ten minutes and 60 min after the onset of CPB in group I (39.5 +/- 16.2% and 40.1 +/- 9.8%, respectively) than in group II (61.1 +/- 16.2% and 61.0 +/- 17.9%, respectively; P <0.05). During CPB, the hepatosplanchnic oxygen extraction ratio was significantly higher in group I than in group II (44.0 +/- 7.2% vs 28.7 +/- 13.1%; P <0.05). CONCLUSION: Hepatosplanchnic oxygenation was better preserved during mild hypothermic CPB than during normothermic CPB.

T cell repertoire in primary biliary cirrhosis: a common T cell clone and repertoire change after treatment.

T cell repertoire was analyzed in three early-stage primary biliary cirrhosis (PBC) patients, using reverse transcription-polymerase chain reaction and single-strand conformation polymorphism. Multiple expanded clones were demonstrated in livers and peripheral blood lymphocytes (PBL) of all three patients. Comparison of the repertoire of different parts of the liver demonstrated the presence of common clones in various Vbeta families. Comparison of the repertoire between the liver and PBL demonstrated that both CD4 and CD8 T cell clones were expanded. Sequence analysis of complementarity determining region 3 of the expanded clones revealed that relatively conserved amino acids were utilized in each patient and that an identical CD4 T cell clone having Vbeta16 was present in all three patients. The number of expanded T cell clones in PBL decreased markedly after the treatment with prednisolone. These results suggest that common T cell clones may play a pathogenic role in PBC.

Energy expenditure after 2- to 3-hour elective surgical operations.

UNLABELLED: Energy expenditure was measured by indirect calorimetry in 17 adult patients (8 women and 9 men) before surgery, 4 hours immediately after surgery, and 24 hours late after surgery in patients undergoing elective surgery of small-to-medium scope. MATERIAL AND METHODS: The total duration of surgery ranged from 2 to 3 hours. Repeated measures were performed on the same patient, so that each patient was considered to be his/her own control. All patients received a 5% dextrose solution (2000 mL/day) throughout the postoperative period. RESULTS: Men showed a reduction in CO2 production during the immediately after surgery period (257+/-42 mL/min) compared to before surgery (306+/-48 mL/min) and late after surgery (301+/-45 mL/min); this reduction was not observed in women. Energy expenditure was also lower in men during immediately after surgery (6.6 kJ/min). None of the other measurements, including substrate oxidation, showed significant differences. CONCLUSION: Therefore, elective surgery itself cannot be considered an important trauma that would result in increased energy expenditure. According to this study, it is not necessary to prescribe an energy supply exceeding basal expenditure during the immediate after-surgery period. The present results suggest that the energy supply prescribed during the postoperative period after elective surgery of small-to-medium scope should not exceed 5-7 kJ/min, so the patient does not receive a carbohydrate overload from energy supplementation.

High frequency of circulating HBcAg-specific CD8 T cells in hepatitis B infection: a flow cytometric analysis.

Viral antigen-specific T cells are important for virus elimination. We studied the hepatitis B virus (HBV)-specific T cell response using flow cytometry. Three phases of HBV infection were studied: Group A, HBeAg (+) chronic hepatitis; Group B, HBeAb (+) HBV carrier after seroconversion; and Group C, HBsAb (+) phase. Peripheral T cells were incubated with recombinant HB core antigen (HBcAg), and intracytoplasmic cytokines were analysed by flow cytometry. HBcAg-specific CD4 and CD8 T cells were identified in all three groups and the number of IFN-gamma-positive T cells was greater than TNF-alpha-positive T cells. The frequency of IFN-gamma-positive CD4 and CD8 T cells was highest in Group C, compared with Groups A and B. No significant difference in the HBcAg-specific T cell response was observed between Group A and Group B. The HBcAg-specific CD8 T cell response was diminished by CD4 depletion, addition of antibody against human leucocyte antigen (HLA) class I, class II or CD40L. Cytokine-positive CD8 T cells without HBcAg stimulation were present at a high frequency (7 of 13 cases) in Group B, but were rare in other groups. HBcAg-specific T cells can be detected at high frequency by a sensitive flow cytometric analysis, and these cells are important for controlling HBV replication.

Aberrant expression of cytokeratin 7 as a histological marker of progression in primary biliary cirrhosis.

AIM: We evaluated the aberrant expression of cytokeratin 7 (CK-7) in hepatocytes as a marker of cholestasis and progression in primary biliary cirrhosis (PBC). PATIENTS AND METHODS: The expression of CK-7 was studied by immunohistochemistry in 83 cases of PBC. This expression was compared with biochemical data, the deposition of copper-associated protein, and previous histological classifications. RESULTS: In normal liver, CK-7 was expressed exclusively in bile duct epithelial cells (BDE). In PBC, the expression was also observed in hepatocytes. The expression pattern was classified as follows: Grade 0, BDE as in normal; Grade 1, proliferated bile ductules; Grade 2, periportal hepatocytes in addition to proliferated bile ductules; Grade 3, intralobular hepatocytes; Grade 4, the majority of hepatocytes. The grades correlated with serum bilirubin levels but not with serum levels of biliary enzymes. A discrepancy between the CK-7 grading and Ludwig's classification was noted in cases with Stage 1 of the CK-7 grading who were considered Stage 2 or 3 in Ludwig's classification, suggesting that cholestasis and inflammatory activity might be independent events. CONCLUSIONS: These results suggest that the aberrant expression of CK-7 in hepatocytes may be a marker of chronic cholestasis and progression in PBC.

Expression of perforin and Fas ligand mRNA in the liver of viral hepatitis.

Cytotoxic T lymphocytes (CTLs) play an important role in the pathogenesis of viral hepatitis. We studied the expression of mRNAs of perforin and Fas ligand (Fas-L) in biopsy specimens from chronic hepatitis B (CHB) (15 cases) and hepatitis C (CHC) patients (13 cases). Both perforin and Fas-L mRNAs were detected in all cases of both CHB and CHC. No messages were detected in the control livers from two cases of fatty liver, a case of Gilbert's syndrome, and a case of Dubin-Johnson syndrome. Semiquantitative analysis revealed a positive correlation between the intensity of perforin and Fas-L mRNAs in both CHB and CHC. In CHB, the intensity of both perforin and Fas-L mRNAs showed a positive correlation with the histological activity and serum alanine aminotransferase level, while the correlation was not apparent in CHC. These results suggest that both perforin and Fas/Fas-L systems are involved in the pathogenesis of liver cell injury of CHB and CHC.

Cerebral oxygenation is better during mild hypothermic than normothermic cardiopulmonary bypass.

PURPOSE: Normothermic cardiopulmonary bypass (CPB) has been recently used in cardiac surgery. However, there is a controversy whether there is a difference in incidence of neurological disorder after coronary artery bypass graft (CABG) surgery between normothermic CPB and mild hypothermic CPB. In this study, we assessed the effects of normothermia and mild hypothermia (32 degrees C) during CPB on jugular oxygen saturation (SjvO2). METHODS: Twenty patients scheduled for elective CABG surgery were divided into two groups. Group 1 (n = 10) underwent normothermic (>35 degrees C) CPB, and Group 2 (n = 10) underwent mild hypothermic (32 degrees C) CPB. Alpha-stat blood gas regulation was applied. After inducing anesthesia, a 4.0 French fibre optic oximetry oxygen saturation catheter was inserted into the right jugular bulb to monitor SjvO2 continuously throughout anesthesia and surgery. RESULTS: The SjvO2 in the normothermic group was decreased at 20 (41.5+/-2.4%) and 40 min (43.8+/-2.8%) after the onset of CPB compared with control (53.9+/-5.4%, P<0.05). However, there was no change in SjvO2 in the mild hypothermic group during the study. No changes in jugular venous-arterial differences of lactate or creatine phosphokinase isoenzyme BB were observed in two groups during the study. CONCLUSIONS: Cerebral oxygenation, as assessed by SjvO2 was increased during mild hypothermic CPB than during normothermic CPB.

Regulatory role of metallothionein in NF-kappaB activation.

Metallothionein (MT), a low molecular weight, cysteine-rich metal binding protein, has been associated with cytoprotection from heavy metals and cellular oxidants. As MT has the ability to scavenge hydroxyl radicals, MT may control intracellular redox status. In the present study, we examined whether MT regulates the activity of nuclear factor-kappaB (NF-kappaB), which is one of the redox-regulated transcription factors, using the MT null embryonic cell lines established from MT null mice. We first found that tumor necrosis factor (TNF)-induced activation of the binding of NF-kappaB protein to DNA in wild type MT+/+ cells was lower than that in MT-/- cells. The NF-kappaB activation in MT-expressing cells established from MT-/- cells by the transfection of mouse MT-1 gene was also significantly lower than that in MT-/- cells. In addition, transfection of the MT gene inhibited TNF-induced IkappaB degradation and suppressed NF-kappaB-dependent gene expression induced by TNF. These results demonstrate that MT may function as a negative regulator of NF-kappaB activity.

Cytokine profile in the liver of primary biliary cirrhosis.

We characterized the cytokine profile in the liver of patients with primary biliary cirrhosis (PBC). Total RNA was extracted from the biopsy specimens of 9 patients with early-stage PBC, 10 with chronic hepatitis C (CHC), and 4 normal controls. cDNA was prepared and amplified with a polymerase chain reaction using primers for interferon (IFN)-gamma and interleukin (IL)-2, -4, -5, -6, -10, -12 (p40), and -15. Cytokines such as IFN-gamma and IL-5, -6, -10, -12, and -15 were expressed in most cases of PBC. Expression rates of IL-5 and IL-6 were higher than in CHC and controls. The higher expression rate of IL-5 in PBC was associated with eosinophil infiltration. IL-2 and IL-4 were rarely detected. Semiquantitative analysis revealed that the expression of IFN-gamma and IL-10 was reversed in PBC and CHC: high IFN-gamma and low IL-10 in PBC and high IL-10 and low IFN-gamma in CHC. These results suggest that cytokine expression is skewed in PBC and both Th1 and Th2 cytokines may play a role in the pathogenesis.