Short-Term Efficacy (at 12 Weeks) and Long-Term Safety (up to 52 Weeks) of Omega-3 Free Fatty Acids (AZD0585) for the Treatment of Japanese Patients With Dyslipidemia　- A Randomized, Double-Blind, Placebo-Controlled, Phase III Study.

BACKGROUND: This study is the first to evaluate the short-term efficacy and long-term safety of AZD0585, a mixture of omega-3 free fatty acids, in Japanese patients with dyslipidemia.Methods and Results:In this randomized double-blind placebo-controlled Phase III study, 383 patients were randomized to 2 g AZD0585, 4 g AZD0585, or placebo once daily for 52 weeks. Eligible patients had low-density lipoprotein cholesterol (LDL-C) levels controlled regardless of statin use, and triglyceride levels between 150 and 499 mg/dL. The least-squares (LS) mean percentage changes in triglyceride concentrations from baseline to the 12-week endpoint (mean of measurements at Weeks 10 and 12) in the 2 and 4 g AZD0585 and placebo groups were -15.57%, -21.75%, and 11.15% respectively (P<0.0001 for both AZD0585 doses vs. placebo). No clinically significant changes from baseline to the 12-week endpoint in total cholesterol, LDL-C, and LDL-C/apolipoprotein (Apo) B were found with AZD0585. High-density lipoprotein cholesterol (HDL-C) was slightly increased and very low-density lipoprotein cholesterol, non-HDL-C, ApoC-II, and ApoC-III were decreased with AZD0585 compared with placebo at the 12-week endpoint. Lipid profiles up to Week 52 were consistent with those up to the 12-week endpoint. No clinically important safety concerns were raised. CONCLUSIONS: AZD0585 significantly decreased serum triglyceride levels compared with placebo at the 12-week endpoint and was generally safe and well tolerated in Japanese patients with dyslipidemia.

Safety and efficacy of verinurad, a selective URAT1 inhibitor, for the treatment of patients with gout and/or asymptomatic hyperuricemia in the United States and Japan: Findings from two phase II trials.

Objective: Evaluate efficacy/safety of verinurad monotherapy in patients with gout (Japan/US) or asymptomatic hyperuricemia (Japan).Methods: Two randomized, placebo-controlled, phase II studies were conducted (NCT01927198/NCT02078219). Patients were randomized to once-daily doses of placebo or escalating doses of verinurad (study 1: 5-12.5 mg; study 2: 2.5-15 mg). Primary endpoint was percentage change from baseline in serum urate (sUA) at week 12 (study 1)/week 16 (study 2). Safety was also assessed.Results: Most patients in study 1 (n = 171) were white (74.9%); all patients were Japanese in study 2 (n = 204). Least squares means (±SE) estimate of percentage change in sUA levels from baseline in study 1 was 1.2 ± 2.9 for placebo, and -17.5 ± 2.8, -29.1 ± 2.8, -34.4 ± 2.9 for verinurad 5, 10, 12.5 mg, respectively. In study 2, results were -2.4 ± 2.5 and -31.7 ± 2.5, -51.7 ± 2.6,-55.8 ± 2.5, respectively. Difference from placebo was significant for each verinurad dose (p<.0001). The proportion of patients with treatment-emergent adverse events (TEAEs) was similar across all groups. Renal-related TEAEs were more common with verinurad than placebo.Conclusion: Verinurad monotherapy resulted in sustained reductions in sUA in Japanese/US patients but renal AEs occurred, so verinurad alone is not recommended for treatment of hyperuricemia or gout. The renal consequences of excessive uric acid excretion deserve study.

Treatment Result of the Mucopexy-Recto Anal Lifting Method for Hemorrhoids in Comparison with Ligation and Excision, and Aluminum Potassium Sulfate and Tannic Acid Sclerotherapy.

The outcomes of Mucopexy-Recto Anal Lifting (MuRAL) in hemorrhoid surgery were compared with ligation and excision (LE), and aluminum potassium sulfate and tannic acid sclerotherapy (ALTA). In this study, we conducted a 3-year follow-up study of MuRAL (380 cases) and compared it with LE (1417 cases) and ALTA (541 cases) performed at the same period. Operative time, mean hospital stay, postoperative pain, postoperative complications, and recurrence were compared and examined retrospectively. The mean operative time was the longest for MuRAL, followed by LE, and then ALTA at 29.1, 21.5, and 12.4 minutes, and the mean length of hospital stay was 6.2, 10.6, and 1.3, days, respectively. Based on the frequency of injectable analgesic use, postoperative pain was clearly milder in MuRAL and ALTA than in LE. The recurrence rates were 3.2% with MuRAL, 1.1% with LE, and 12.4% with ALTA. Early postoperative low-grade fever and bowel movement urgency were observed in all surgeries, but these were minor and did not pose a safety problem. LE is painful and requires prolonged hospitalization but is the most curative; ALTA is simple and can be performed as a day surgery but has a high recurrence rate. MuRAL was less painful than LE and had a lower recurrence rate than ALTA. In recent years, there have been various innovations in the surgical treatment of hemorrhoids, and choosing a technique that is appropriate for the condition of the hemorrhoid and patient's needs is necessary. MuRAL can be one of the options for hemorrhoid treatment as a "cure without cutting" method.

Clinical Significance of the Left Atrial Appendage Orifice Area.

Objective The left atrial appendage (LAA) is one of the major sources of cardiac thrombus formation. Three-dimensional transesophageal echocardiography (TEE) made it possible to perform a detailed evaluation of the LAA morphologies. This study aimed to evaluate the clinical implications of the LAA orifice area. Methods A total of 149 patients who underwent TEE without significant valvular disease were studied. The LAA orifice area was measured using three-dimensional TEE. The patients were divided into two groups according to the LAA orifice area (large LAA orifice group, ≥median value, and small LAA orifice group). The clinical characteristics and echocardiographic findings were evaluated. Results The median LAA orifice area among all patients was 4.09 cm2 (interquartile range 2.92-5.40). The large LAA orifice group were older (67.2±10.4 vs. 62.4±15.3 years, p=0.02), more often had hypertension (66.7% vs. 44.6%, p=0.007), and atrial fibrillation (70.7% vs. 39.2%, p<0.001) than the small LAA orifice group. Regarding the TEE findings, the LAA flow velocity was significantly lower (33.7±20.0 vs. 50.2±24.3, p<0.001) and spontaneous echo contrast was more often observed (21.3% vs. 8.1%, p=0.02) in the large LAA orifice group. Multivariate models demonstrated that atrial fibrillation was an independent predictor of the LAA orifice area. In the analysis of atrial fibrillation duration, the LAA orifice area tended to be larger as patients had a longer duration of atrial fibrillation. Conclusion Our findings indicated that a larger LAA orifice area was associated with the presence of atrial fibrillation and high thromboembolic risk based on TEE findings. A continuation of the atrial fibrillation rhythm might lead to the gradual expansion of the LAA orifice.

A multicenter phase II clinical study of oxaliplatin, folinic acid, and 5-fluorouracil combination chemotherapy as first-line treatment for advanced colorectal cancer: a Japanese experience.

PURPOSE: This multicenter phase II study was designed to determine the efficacy and tolerability of oxaliplatin in combination with levofolinate and infusion 5-fluorouracil (FOLFOX4) as first-line therapy for Japanese patients with unresectable metastatic colorectal cancer. METHODS: Sixty consecutive patients with histologically confirmed advanced or metastatic colorectal cancer were enrolled in the study. Treatment was repeated every 2 weeks until disease progression or unacceptable toxicity occurred. RESULTS: Two patients were ineligible. Toxicity was evaluated in 60 patients, who had received a part or all of the protocol therapy. A partial response was observed in 20 patients. The overall response rate was 34.5% (95% CI, 22.5%-48.1%) and the tumor control rate (partial response + stable disease) was 82.8%. The median progression-free survival was 6.9 months (95% CI, 5.1-9.8 months), and the median overall survival was 31.5 months (95% CI, 18.1-40.1 months). There were no toxicity-related deaths. Grade 3 or 4 neutropenia occurred in 48.3% of patients and often caused a delay in the subsequent treatment course. Mild to moderate cumulative peripheral sensory neuropathy affected 71.7% of patients. CONCLUSION: The results showed good tolerability and efficacy for first-line FOLFOX4 in the treatment of patients with advanced colorectal cancer, indicating the promise of this regimen as first-line therapy for advanced colorectal cancer in the Japanese population.

Relationship between epicardial adipose tissue volume and coronary artery spasm.

BACKGROUND: Epicardial adipose tissue (EAT) is considered to play a critical role in vascular endothelial function. Coronary artery spasm has been postulated to be a causal factor in vascular endothelial abnormalities and atherosclerosis. This study aimed to investigate the relationship between coronary artery spasm and EAT volume, total abdominal adipose tissue (AAT) area, and abdominal visceral adipose tissue (AVAT) area. METHOD: Among patients undergoing coronary computed tomography (CT) to evaluate coronary artery disease, we identified 110 patients who did not have significant coronary artery stenosis and underwent a coronary spasm provocation test with cardiac catheterization. They were divided into two groups according to the results of the spasm provocation test: spasm-positive and spasm-negative. EAT volume, total AAT area, and AVAT area were evaluated using CT images. RESULTS: Seventy-seven patients were included in the spasm-positive group and 33 patients in the spasm-negative group. There were no significant differences in baseline clinical characteristics between the two groups, except for the prevalence of current smoking (48% vs. 27%, p = 0.04). EAT volume was significantly higher in the spasm-positive group (108 ±â€¯38 mL vs. 87 ±â€¯34 mL, p = 0.007), while no significant difference was seen in total AAT area (280 ±â€¯113 cm2 vs. 254 ±â€¯128 cm2, p = 0.32) or AVAT area (112 ±â€¯54 cm2 vs. 98 ±â€¯55 cm2, p = 0.27). Multivariate logistic analysis indicated that EAT volume (per 10 cm3) (odds ratio, 1.198; 95% confidence interval, 1.035-1.388; p = 0.016) was a significant predictor of coronary artery spasm. CONCLUSION: Our results suggest that EAT has a strong association with coronary artery spasm, while AAT may not.

The Influence of Eicosapentaenoic Acid to Arachidonic Acid Ratio on Long-term Cardiovascular Events Following Percutaneous Coronary Intervention.

Objective The relationship between cardiovascular disease and the serum polyunsaturated fatty acid parameters has been reported. The aim of the present study was to investigate the association between the eicosapentaenoic acid and arachidonic acid (EPA/AA) ratio and long-term cardiovascular events in patients with coronary artery disease. Methods We identified a total of 831 patients who underwent percutaneous coronary intervention and whose EPA/AA ratio was available. The patients were divided into two groups according to their serum EPA/AA ratio (median, 0.29; interquartile range 0.19-0.47): those in the lower quartile of EPA/AA ratios (Low EPA/AA group; n=231) and all other subjects (High EPA/AA group; n=600). The primary endpoints included a composite of cardiovascular death, myocardial infarction, and ischemic stroke. Results Patients in the Low EPA/AA group were significantly younger (66.0±12.6 years vs. 69.9±9.3 years, p<0.001), current smokers (33.3% vs. 22.7%, p=0.002), and had a history of myocardial infarction (20.3% vs. 12.3%, p=0.003). During the follow-up (median, 1,206 days; interquartile range, 654-1,910 days), the occurrence of the primary endpoint was significantly higher in the Low EPA/AA group than in the High EPA/AA group. Of note, the rate of cardiovascular death was significantly higher in the Low EPA/AA group, and the rates of myocardial infarction and stroke tended to be higher. Conclusion A low EPA/AA ratio was associated with long-term adverse cardiovascular events in Japanese patients with coronary artery disease.

Clinical outcomes following percutaneous coronary intervention for bifurcation lesions: kissing balloon inflation vs. sequential dilation.

Percutaneous coronary intervention for bifurcation lesions remains challenging, with there being several debatable issues, including the requirement for kissing balloon inflation (KBI). The objective of this study was to assess the clinical outcomes following single crossover stent implantation with KBI or sequential dilation alone. Data were examined for 255 non-left main bifurcation lesions (246 patients) treated with single crossover stent implantation, followed by side branch (SB) strut dilation with KBI (n = 74 lesions) or sequential dilation (n = 181 lesions) in three hospitals. Target lesion revascularization (TLR) was the primary endpoint. There was no significant difference in the pre-procedural reference diameter of both the main vessel (MV) and SB between the KBI and sequential dilation groups. However, MV post-dilation balloon size was smaller with lower pressure and post-procedural minimal lumen diameter was significantly smaller in the KBI group. During the median follow-up period of approximately 3 years, TLR incidence was significantly higher in the KBI group than in the sequential dilation group; in particular, the TLR rate at the distal MV was higher in the former. For bifurcation lesions treated with single crossover stent implantation, the TLR rate was higher after KBI than after sequential dilation; this was mainly due to higher revascularization in the distal MV. For bifurcation lesions treated with KBI, MV post-dilation balloon diameter tended to be smaller with lower pressure, which might lead to poorer stent expansion and a higher TLR rate.

Lipid-rich large plaques in a non-culprit left main coronary artery and long-term clinical outcomes.

BACKGROUND: An integrated backscatter (IB) intravascular ultrasound (IVUS) provides an information about tissue components and vulnerability of coronary plaques. The presence of vulnerable plaque in non-culprit lesion is associated with future clinical events. The purpose of this study was to assess the association between the characteristics of non-culprit left main coronary artery (LMCA) plaques evaluated by IB-IVUS and long-term clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). METHODS: Among the patients who underwent non-LMCA PCI, we studied 366 patients with adequate LMCA IVUS images. Conventional and IB-IVUS analyses of the LMCA segment were performed. Lipid-rich large plaque was defined as the presence of both a lager plaque volume and a higher percentage of the lipid component than the obtained median values. Major adverse cardiovascular events (MACE) included cardiac death, myocardial infarction, and unplanned revascularization. RESULTS: The mean age of the patients was 68.5 ± 10.2 years, 79.8% were men. Median follow-up period was 6.0 years (IQR: 4.2-8.1 years). The incidence of MACE was significantly higher in patients with lipid-rich large plaques (P = .006). The incidence rates of cardiac death, myocardial infarction, and unplanned revascularization were significantly higher in patients with lipid-rich large plaques (P = .02, 0.004, and 0.02, respectively). Multivariate Cox regression analysis showed that the presence of a lipid-rich large plaque was significantly associated with MACE (HR: 1.74; 95%CI: 1.17-2.58; P = .006). CONCLUSION: The presence of lipid-rich large plaques in a non-culprit LMCA can be associated with the long-term MACE in patients who have undergone PCI.

Impact of Diabetes Mellitus on the Aortic Wall Changes as Atherosclerosis Progresses: Aortic Dilatation and Calcification.

AIM: An inverse association between diabetes mellitus (DM) and aortic dilatation has recently been reported. However, little is known about the association between DM and the progression of aortic dilatation/calcification as atherosclerosis progresses. METHODS: We identified 216 patients who had undergone percutaneous coronary intervention (PCI) and abdominal computed tomography (CT) during the PCI and follow-up phases. The patients were classified into two groups: those with DM (DM+ group; n=107) and those without DM (DM- group; n=109). The infrarenal aortic diameter and aortic calcification index (ACI) were measured, and annual changes were calculated using measurement results obtained during the PCI and follow-up phases. RESULTS: Infrarenal aortic diameters were significantly shorter in the DM+ group than in the DM- group during the PCI phase, and no significant ACI differences were observed between the DM+ and DM- groups. The median duration between the PCI and follow-up phase CT was 3.0 years. The growth rate of the infrarenal aortic dilatation from the PCI phase in the DM+ group was similar to that in the DM- group. Annual ACI changes were significantly larger in the DM+ group than in the DM- group. Multivariate logistic regression analysis indicated that the prevalence of DM was an independent predictor of rapid aortic calcification progression (odds ratio: 2.51; 95% confidence interval: 1.23-5.14; p=0.01). CONCLUSION: Our findings suggest that DM negatively affects aortic dilatation during an earlier phase of atherosclerosis progression and positively affects the progression of aortic calcification in a later phase.

Prognostic impact of recanalizing chronic total occlusion in non-infarct related arteries on long-term clinical outcomes in acute myocardial infarction patients undergoing primary percutaneous coronary intervention.

Although chronic total occlusion (CTO) in non-infarct-related arteries (non-IRAs) negatively affects long-term mortality in patients with acute myocardial infarction (AMI) who are undergoing primary percutaneous coronary intervention (PCI), the prognostic impact of successful CTO-PCI has not been completely addressed. Among 1855 consecutive patients with AMI who underwent primary PCI, those who were treated for CTO with either PCI or medical therapy were included. We evaluated the association between recanalization of CTO and long-term cardiac mortality. Of the 172 included patients, 88 underwent CTO-PCI, and the procedures were successful in 65 patients. Thus, the successfully recanalized CTO (SR-CTO) group included 65 patients; and the no recanalized CTO (NR-CTO) group, 107 patients. During the follow-up, 72 patients died, and of whom 56 (77.8%) died because of cardiac causes. The cumulative 10-year, 30-day, and 30-day to 10-year incidences of cardiac mortality were lower in the SR-CTO group than in the NR-CTO group (19.0% vs. 51.9% p = 0.004; 4.6% vs. 14.0%, p = 0.05; 15.0% vs. 44.1%, p = 0.003, respectively). After adjusting for confounding factors, the benefits of SR-CTO for the 10-year cardiac mortality remained significant compared with those of NR-CTO (hazard ratio 0.37; 95% confidence interval 0.17-0.75; p = 0.004). In conclusion, patients with SR-CTO in non-IRAs after AMI was associated with reduced long-term cardiac mortality compared with those with NR-CTO.

Regional vulnerability to chronic hypoxia and chronic hypoperfusion in the rat brain.

The purpose of this study was to compare the pathological findings of injury induced by chronic hypoperfusion and by chronic hypoxia in rat brain. Adult male Wistar rats were divided into three groups: chronic hypoperfusion (n=5), chronic hypoxia (n=5), and normal control groups (n=5). Hypoperfusion was induced by ligation of the bilateral carotid arteries under 2.5% halothane anesthesia. Chronic hypoxia was induced by keeping the animals in a chamber with an atmosphere of 10% O(2) in N(2) for 3 weeks. Twelve weeks later (chronic hypoperfusion group) and 3 weeks later (chronic hypoxia group), the animals were sacrificed and perfused through the femoral artery with a fixative containing 4% paraformaldehyde. Hematoxylin and eosin staining was done in all sections in the three groups, and the number of normal-appearing cells was counted. Normal-appearing cells in CA3 were significantly decreased in the chronic hypoperfusion group compared with those in the chronic hypoxia group, although neurons in CA1, CA2 and CA4 in both groups were equally damaged. We concluded that the CA3 hippocampus shows different vulnerabilities to chronic hypoperfusion and chronic hypoxia, possibly owing to a difference in the kinds of glutaminergic receptors.

[A case of recurrent meningitis with association of human herpes virus-6 hepatitis].

A 27-year-old man presenting with recurrent meningitis associated with the activation of hepatitis was reported. Although he showed headache only, he was diagnosed as viral meningitis with high transaminase activities on admission. Human herpes virus-6 (HHV-6) DNA was revealed in the liver tissue by the polymerase chain reaction. This case was considered viral meningitis with HHV-6 associated hepatitis. It is suggested that the importance of viral evaluations not only herpes virus type 1 x 2, cytomegaro virus and EB virus, but also HHV-6 infection in a case of recurrent meningitis with hepatitis simultaneously.

Pelvic exenteration and sacral resection for locally advanced primary and recurrent rectal cancer.

PURPOSE: The only possibility of a surgical cure in patients with locally advanced primary or recurrent rectal cancer would be an extended resection such as pelvic exenteration and sacral resection. The aim of this study was to evaluate the safety, tolerability, and survival benefits of these procedures. METHODS: Between 1988 and 1999, 64 patients with locally advanced primary or recurrent rectal cancer underwent abdominoperineal resection, with sacral resection in 9 patients, anterior pelvic exenteration in 8 patients, total pelvic exenteration in 27 patients, and total pelvic exenteration with sacral resection in 20 patients. RESULTS: Rates of morbidity, reoperation, and mortality were 50, 4.5, and 0 percent in 22 patients with primary cancer, and 60, 2.4, and 2.4 percent in 42 patients with recurrent disease, respectively. Major complications, such as sepsis, intra-abdominal abscess, and enteric fistula caused one hospital death and reoperation in two patients. In 21 patients who underwent curative resection for primary cancer, the overall five-year survival rates were 74.1 percent for Dukes B and 47.4 percent for Dukes C, although the difference was not statistically significant. Thirty patients with recurrent cancer who underwent curative resection had significantly improved survival, with a five-year survival rate of 22.9 percent, compared with 12 patients who underwent palliative resection, resulting in a survival rate of 0 percent (P = 0.0065). CONCLUSIONS: Pelvic exenteration and sacral resection for primary or recurrent rectal cancer are tolerable procedures with a low mortality rate. Although they provide a survival benefit if curative resection is possible, the associated morbidity remains high and should be followed up closely.

Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein.

The amyloid-beta (A beta) peptide, which is derived from the amyloid precursor protein (APP), is involved in the pathogenesis of Alzheimer's dementia and impairs endothelium-dependent vasodilation in cerebral vessels. We investigated whether cerebrovascular autoregulation, i.e., the ability of the cerebral circulation to maintain flow in the face of changes in mean arterial pressure (MAP), is impaired in transgenic mice that overexpress APP and A beta. Neocortical cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized APP(+) and APP(-) mice. MAP was elevated by intravenous infusion of phenylephrine and reduced by controlled exsanguination. In APP(-) mice, autoregulation was preserved. However, in APP(+) mice, autoregulation was markedly disrupted. The magnitude of the disruption was linearly related to brain A beta concentration. The failure of autoregulation was paralleled by impairment of the CBF response to endothelium-dependent vasodilators. Thus A beta disrupts a critical homeostatic mechanism of the cerebral circulation and renders CBF highly dependent on MAP. The resulting alterations in cerebral perfusion may play a role in the brain dysfunction and periventricular white-matter changes associated with Alzheimer's dementia.

Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein.

We have used quantitative autoradiographic techniques to study the relationship between cerebral blood flow (CBF) and glucose utilization (CGU) in two lines of transgenic mice overexpressing Swedish mutant amyloid precursor protein (APP) and APP-derived Abeta peptides. Mice were studied at an age when there are no amyloid plaques. In the 2123 line, CBF was reduced only in telencephalic regions with no corresponding decrease in CGU. In 2576 transgenics, a line with higher levels of Abeta peptide, both CBF and CGU were reduced throughout the brain. The data indicate that Abeta induces alterations in resting CBF that are either associated with or independent of alterations in CGU and that occur in the absence of amyloid deposition in neuropil of blood vessels. These observations support the hypothesis that cerebrovascular and metabolic abnormalities are early events in the pathogenesis of Alzheimer's disease.

Prostanoids, not reactive oxygen species, mediate COX-2-dependent neurotoxicity.

The prostaglandin synthesizing enzyme cyclooxygenase-2 (COX-2) has emerged as a critical pathogenic factor in brain diseases associated with activation of N-methyl-D-aspartate (NMDA) receptors, including stroke and neurodegenerative diseases. However, the COX-2 reaction products responsible for these deleterious effects have not been identified. In particular, the relative contribution to the neurotoxicity of COX-2-derived prostanoids and reactive oxygen species has not been defined. We found that the brain damage produced by direct injection of NMDA into the somatosensory cortex is attenuated by the COX-2 inhibitor NS-398 or in COX-2-null mice, but that the associated production of free radicals is not. Furthermore, COX-2 inhibition reduces the lesions even if the deleterious effects of free radicals are eliminated by the scavenger superoxide dismutase. The protection exerted by NS-398 is counteracted by a stable analog of prostaglandin E2. The findings directly implicate COX-2-derived prostanoids, rather then radicals, in the COX-2-dependent component of the damage mediated by NMDA receptors and strengthen the rationale for using COX-2 inhibitors in the treatment of neurological diseases associated with glutamate neurotoxicity.