S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial.

Background: Combination therapy with oral fluoropyrimidine and irinotecan has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). We carried out a randomized, open-label, phase III trial to determine whether S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab in terms of progression-free survival (PFS). Patients and methods: Patients from 53 institutions who had previously untreated mCRC were randomly assigned (1 : 1) to receive either mFOLFOX6 or CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; a 3-week regimen: intravenous infusions of irinotecan 150 mg/m2 and bevacizumab 7.5 mg/kg on day 1, oral S-1 80 mg/m2 twice daily for 2 weeks, followed by a 1-week rest; or a 4-week regimen: irinotecan 100 mg/m2 and bevacizumab 5 mg/kg on days 1 and 15, S-1 80 mg/m2 twice daily for 2 weeks, followed by a 2-week rest). The primary end point was PFS. The noninferiority margin was 1.25; noninferiority would be established if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) of the control group versus the experimental group was less than this margin. Result: Between June 2012 and September 2014, 487 patients underwent randomization. Two hundred and forty-three patients assigned to the control group and 241 assigned to the experimental group were included in the primary analysis. Median PFS was 10.8 months (95% CI 9.6-11.6) in the control group and 14.0 months (95% CI 12.4-15.5) in the experimental group (HR 0.84, 95% CI 0.70-1.02; P < 0.0001 for noninferiority, P = 0.0815 for superiority). One hundred and fifty-seven patients (64.9%) in the control group and 140 (58.6%) in the experimental group had adverse events of grade 3 or higher. Conclusion: S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab with respect to PFS as first-line treatment of mCRC and could be a new standard treatment. Clinical trials number: UMIN000007834.

A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC).

BACKGROUNDS: Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. PATIENTS AND METHODS: The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. RESULTS: In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. CONCLUSION: One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection.

The application of omics technologies in the functional evaluation of inulin and inulin-containing prebiotics dietary supplementation.

Inulin, a natural renewable polysaccharide resource produced by various plants in nature, has been reported to possess a significant number of diverse pharmaceutical and food applications. Recently, there has been rapid progress in high-throughput technologies and platforms to assay global mRNA, proteins, metabolites and gut microbiota. In this review, we will describe the current status of utilizing omics technologies of elucidating the impact of inulin and inulin-containing prebiotics at the transcriptome, proteome, metabolome and gut microbiome levels. Although many studies in this review have addressed the impact of inulin comprehensively, these omics technologies only enable us to understand physiological information at each different stage of mRNA, protein, metabolite and gut microbe. We believe that a synergistic approach is vital in order to fully illustrate the intricate beauty behind the relatively modest influence of food factors like inulin on host health.

Randomized clinical trial of skin closure by subcuticular suture or skin stapling after elective colorectal cancer surgery.

BACKGROUND: The best suture method to prevent incisional surgical-site infection (SSI) after clean-contaminated surgery has not been clarified. METHODS: Patients undergoing elective colorectal cancer surgery at one of 16 centres were randomized to receive either subcuticular sutures or skin stapling for skin closure. The primary endpoint was the rate of incisional SSI. Secondary endpoints of interest included time required for wound closure, incidence of wound problems, postoperative length of stay, wound aesthetics and patient satisfaction. RESULTS: A total of 1264 patients were enrolled. The cumulative incidence of incisional SSI by day 30 after surgery was similar after subcuticular sutures and stapled closure (8·7 versus 9·8 per cent respectively; P = 0·576). Comparison of cumulative incidence curves revealed that SSI occurred later in the subcuticular suture group (P = 0·019) (hazard ratio 0·66, 95 per cent c.i. 0·45 to 0·97). Wound problems (P = 0·484), wound aesthetics (P = 0·182) and postoperative duration of hospital stay (P = 0·510) did not differ between the groups; subcuticular sutures took 5 min longer than staples (P < 0·001). Patients in the subcuticular suture group were significantly more satisfied with their wound (52·4 per cent versus 42·7 per cent in the staple group; P = 0·002). CONCLUSION: Compared with skin stapling, subcuticular sutures did not reduce the risk of incisional SSI after colorectal surgery. REGISTRATION NUMBER: UMIN000004001 (http://www.umin.ac.jp/ctr).

The indications for a diverting stoma in low anterior resection for rectal cancer: a prospective multicentre study of 222 patients from Japanese cancer centers.

AIM: The aim of the study was to determine the present state of diverting stoma construction in Japanese cancer centres and to investigate the relationship between symptomatic leakage and diverting stoma after low anterior resection for rectal cancer. METHOD: Two hundred and twenty-two consecutive patients undergoing low anterior resection for rectal cancer located within 10 cm from the anal verge were investigated in a prospective, multicenter study. RESULTS: The overall leakage rate was 9.0% (20/222). Of 31 cases with an anastomosis within 2.0 cm from the anal verge, 22 (71%) had a diverting stoma. Of cases anastomosed within 5.0 cm, the absence of a diverting stoma and tumour size were significantly related to an increased rate of leakage [leakage in 13 (12.7%) of 102 cases without a diverting stoma; in three (3.8%) of 80 cases with a diverting stoma]. Among anastomoses within 2.0 cm from the anal verge, leakage occurred in four (44.4%) of nine cases without and in none (0%) of 22 cases with a diverting stoma. CONCLUSION: We recommend a diverting stoma for an anastomosis within 5.0 cm of the anal verge and strongly recommend it for a very low anastomosis within 2.0 cm.

Discovery of a potent, metabolically stabilized resorcylic lactone as an anti-inflammatory lead.

With bioactivity-guided phenotype screenings, a potent anti-inflammatory compound f152A1 has been isolated, characterized and identified as the known natural product LL-Z1640-2. Metabolic instability precluded its use for the study on animal disease models. Via total synthesis, a potent, metabolically stabilized analog ER-803064 has been created; addition of the (S)-Me group at C4 onto f152A1 has resulted in a dramatic improvement on its metabolic stability, while preserving the anti-inflammatory activities.

Acyclic carotenoids and their oxidation mixtures inhibit the growth of HL-60 human promyelocytic leukemia cells.

Lycopene has been known as a potential food component for cancer prevention, since tomato consumption was shown to be associated with reduced risk of certain cancers. We used HL-60 cells as a model of cancer cells to investigate whether acyclic carotenoids, such as phytoene, phytofluene, and zeta-carotene present in tomatoes, other than lycopene, as well as oxidation mixtures of these carotenoids, are potentially involved in the cancer-preventive action of tomatoes. When HL-60 cells were grown in the carotenoid-supplemented medium for 120 hours, zeta-carotene and phytofluene at 10 microM inhibited cell growth to 3.7% and 22.6% of the growth in control culture, respectively, although they were extremely unstable in the culture medium. The oxidation mixture of each carotenoid, which was prepared by incubation in toluene at 37 degrees C for 24 hours, more strongly inhibited cell growth than each intact carotenoid. The growth inhibition by lycopene was remarkably enhanced by its oxidation before supplementation to the medium. Phytofluene, zeta-carotene, and the oxidation mixture of lycopene induced apoptosis in HL-60 cells during incubation for 24 hours. The addition of alpha-tocopherol to the medium did not eliminate growth inhibition by the oxidation mixture of lycopene. These results suggest that the acyclic carotenoids inhibit cell growth through apoptosis induction and that oxidation products of the carotenoids participate in the growth inhibition.

Reverse transcriptase is elevated in the thyroid tissue from Graves' disease patients.

OBJECTIVE: Hypertrophy of the thyroid gland in Graves' disease is related to an autoimmune response directed against TSH receptors found in thyroid cells. Recently, investigators have suggested that autoimmune diseases, including thyroid diseases may, at least in part, correlate with the expression of proteins encoded by the retroviral genome. In the present study, to confirm the correlation between thyroid autoimmune disorders and retroviral infections, we examined reverse transcriptase (RT) activity in thyroid tissues as a marker of retroviral infection. PATIENTS AND MEASUREMENTS: Thyroid tissues obtained at surgery from patients with various thyroid disorders (normal thyroid adjacent to adenoma, six cases; Graves' disease thyroid tissue, 25 cases; adenoma, eight cases; papillary carcinoma, 12 cases; Graves' disease peripheral blood lymphocytes, 11 cases) were used for RT assay, using a specific, improved assay system. RESULTS: Thyroid tissue extracts from patients with Graves' disease contained high RT activity which resembled that demonstrated in retroviruses. The RT existed in the thyroid tissue as a complex, with endogenous template RNA, and the activity was confirmed not to be due to other DNA polymerases. CONCLUSION: Retroviral RT distinguished from known cellular DNA polymerases is expressed in the thyroids of patients with Graves' disease. In a permissive genetice and immunological environment, retroviral DNA integrated into genomic DNA could precipitate the onset of Graves' disease.

Preprimed artificial lung for emergency use.

We investigated the possibility of preprimed storage of an artificial lung (AL), aiming at facilitating its emergency use. Test ALs, consisting of a special microporous hollow fiber membrane made of polyolefin in which direct blood-gas contact was completely eliminated, were preprimed with saline solution, sterilized by gamma-ray irradiation, and evaluated after 1-3 months of storage at room temperature. A small amount of bubble was noted in the priming solution after storage in some ALs, which most likely originated from the air dissolved in the priming solution or persisted in the liquid compartment at priming. Although the preprimed solution contained several polyolefin-breakdown products due to irradiation, including ethyl alcohol, n- and t-butyl alcohol, acetone, and carbon dioxide, the levels of these substances were at concentrations known to be not toxic. Endotoxin concentration was negligible. In SEM observation, no perceptible microstructural change was observed in the hollow fibers after preprimed storage. Maximum tensile stress and ultimate elongation of the hollow fiber in the test ALs were reduced by approximately 20% and 3%, respectively, from those of the control AL. The influence of preprimed storage on gas-exchange function was examined in a venoarterial bypass animal study using a goat. Oxygen transfer function was well preserved whereas carbon dioxide removal function was slightly lowered according to the storage term in the stored ALs compared with those of a nonpreprimed control AL. On the basis of these results, we conclude that preprimed storage of the AL with gamma-ray sterilization is basically feasible and realistic.

A formal total synthesis of (-)-cephalotaxine.

A formal total synthesis of (-)-cephalotaxine (1) has been achieved. The key step is an intramolecular aldol condensation of the diketone 9, which in turn was obtained in three steps from the azabicyclic compound 6 derived from D-proline according to Seebach's procedure. Treatment of 9 with a catalytic amount of sodium 2-methyl-2-butanolate in benzene at room temperature gave the alpha, beta-unsaturated ketone 8 in 43% yield. Catalytic hydrogenation of 8 followed by reduction of the ketone 22 with sodium borohydride and acetylation of the resulting alcohol 23 gave the acetoxy derivative 24, which, after deprotection, was acylated with (methylthio)acetic acid to give the amide 26. Compound 26 was converted into optically active ketolactam 4 following the synthetic operations developed for the synthesis of the racemic compound.

Glucose transporter 2 concentrations in hyper- and hypothyroid rat livers.

The deterioration of glucose metabolism frequently observed in hyperthyroidism may be due in part to increased gluconeogenesis in the liver and glucose efflux through hepatocyte plasma membranes. Glucose transporter 2 (GLUT 2), a facilitative glucose transporter localized to the liver and pancreas, may play a role in this distorted glucose metabolism. We examined changes in the levels of GLUT 2 in livers from rats with l-thyroxine-induced hyperthyroidism or methimazole-induced hypothyroidism by using Western blotting to detect GLUT 2. An oral glucose tolerance test revealed an oxyhyperglycemic curve (impaired glucose tolerance) in hyperthyroid rats (n=7) and a flattened curve in hypothyroid rats (n=7). GLUT 2 levels in hepatocyte plasma membranes were significantly increased in hyperthyroid rats and were not decreased in hypothyroid rats compared with euthyroid rats. The same results were obtained with a densitometric assay. These findings suggest that changes in the liver GLUT 2 concentration may contribute to abnormal glucose metabolism in thyroid disorders.

Reduction of activity, but no decrease in concentration, of erythrocyte Cu,Zn-superoxide dismutase by hyperglycaemia in diabetic patients.

Cu,Zn-superoxide dismutase(SOD) activity in erythrocytes is affected by various diseases, including diabetes mellitus (DM). We investigated changes in the Cu,Zn-SOD activity compared to changes in the Cu,Zn-SOD concentration in erythrocytes obtained from patients with Type 2 (non-insulin-dependent) diabetes mellitus. Cu,Zn-SOD activity in erythrocytes was significantly lower in Type 2 DM patients than in healthy non-diabetic subjects. The activity correlated negatively with HbA1c, but not with other indicators of metabolic control, such as fasting blood glucose or plasma cholesterol or triglyceride. However, there was no statistically significant difference in erythrocyte concentration of Cu,Zn-SOD between diabetic and control samples. Concentration did not correlate with enzymatic activity or HbA1c. These findings indicate that the inactivation of Cu,Zn-SOD activity in erythrocytes of Type 2 DM patients by hyperglycaemia may be slow, because there is a negative correlation between the enzyme activities and HbA1c levels, but not fasting blood glucose levels. This is consistent with glycosylation of the active site of Cu,Zn-SOD, without any effect of hyperglycaemia on the concentration of Cu,Zn-SOD.

Effects of thyroid hormone on catecholamine and its metabolite concentrations in rat cardiac muscle and cerebral cortex.

Clinical and experimental data suggest that thyroid hormone affects the actions of catecholamine (CA). However, the serum or tissue levels of CA during thyroid disorders have not been well defined. Accordingly, we investigated the levels of CA and their metabolites in the cardiac muscle, the cerebral cortex, and the plasma of rats with hyperthyroidism and hypothyroidism versus euthyroid animals. The Neurochem analyzer system (ESA, Inc., Bedford, MA) was used in such determinations. The cardiac muscles of hyperthyroid rats exhibited a 16% decrease in the levels of 1-dopa, 3-methoxytyramine (3-MT) and homovanillic acid (HVA) as compared with those in euthyroid rats. The levels of norepinephrine (NE) in cardiac muscle of these rats increased significantly (5.2-fold) relative to the levels in euthyroid rats. NE was undetectable in the cardiac muscles of the hypothyroid rats. Epinephrine (E) and dopamine (DA) were not detected in the cardiac muscles of the rats with either thyroid disorder. Levels of E and 3,4-dihydroxymandelic acid (DOPEG) were detected only in the cerebral cortex of hyperthyroid rats. The cerebral cortex levels of 3-methyoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), metanephrine (MN), and homovanillic acid (HVA) were all significantly increased in the hyperthyroid versus the euthyroid rats. The cerebral cortex levels of DA, NE, normetanephrine (NMN), and VMA in the hyperthyroid rats all showed a significant decrease. Levels of NE, NMN, and DOPAC in the cerebral cortex increased significantly in the hypothyroid rats. The level of VMA was undetectable in cerebral cortex of such animals. Data from studies on cardiac muscle and cerebral cortex indicate that the changes in CA and CA metabolites are responsible in part for the cardiovascular and the central nervous system symptoms observed in hyperthyroidism and hypothyroidism.

Alteration of platelet aggregation in patients with thyroid disorders.

To determine whether Graves' disease or primary hypothyroidism influence platelet function, we evaluated platelet aggregation in the platelet-rich plasma (PRP) from such patients. Platelet aggregation induced by adenosine diphosphate (ADP) in blood obtained from patients with untreated Graves' disease was significantly lower than normal, whereas that in patients with untreated primary hypothyroidism was relatively increased. The magnitude of platelet aggregation induced by collagen in both groups of patients resembled that induced by ADP. However, significant differences were evident between the two diseases (P < .05). In addition, we observed a significant inverse correlation between the extent of platelet aggregation and plasma levels of thyroid hormones (triiodothyronine [T3], thyroxine [T4], and free T3). Platelet aggregation returned to normal when the euthyroid condition was obtained in the patients following administration of antithyroid drugs or thyroid hormone. The findings are consistent with the possibility that thyroid hormones influence platelet aggregation partly via inhibition of myosin light-chain kinase (MLCK).

Changes in free radical scavengers and lipid peroxide in thyroid glands of various thyroid disorders.

To clarify whether the changes of free radicals and its scavengers are induced by thyroid disorders, we measured levels of free radical scavengers and checked O2 radical generating systems in the human thyroid gland. Thyroid specimens from patients with Graves' disease, follicular adenoma, and papillary and follicular carcinomas contained significantly higher concentrations of xanthine oxidase (XOD) and gluthathione peroxidase (GSH-PX), compared to those in the normal thyroid tissue. Catalase concentration was significantly lower in thyroid specimens from patients with Graves' disease and significantly lower in thyroid specimens from patients with follicular adenoma, compared to those in the normal thyroid tissue. Cu/Zn superoxide dismutase (Cu/Zn SOD) concentration was significantly lower in the specimens from follicular adenoma and papillary carcinoma and Mn SOD concentration was significantly higher in the specimens from papillary carcinoma than those in the normal thyroid tissue. The lipid peroxide concentration, expressed as malondialdehyde (MDA) concentration, was significantly higher in the specimens from papillary carcinoma than those in the normal thyroid tissue. These findings suggest that the levels of free radicals are increased and are scavenged and catalyzed in the thyroid of Graves' disease, whereas free radicals and lipid peroxide are not completely scavenged in papillary carcinoma tissues, suggesting that these substances affect some role in cell function of thyroid tumors.

Fatigue resistance of titanium-nickel alloy cast clasps.

In this study fatigue resistance of experimentally prepared titanium-nickel (50.8% nickel and 49.2% titanium) cast clasps was evaluated in a simulated clinical situation. The change in force required to remove the titanium-nickel clasps was recorded under a repeated placement-and-removal test on steel model abutment teeth. Commercially-pure titanium, cobalt-chromium alloy, and gold-silver-palladium-copper alloy clasps were also tested for comparison. The tips of the clasps were located in the 0.25- and 0.50-mm undercut areas of the abutments. No significant changes in the retentive force were found in titanium-nickel clasps in the 1,010 repeated cycles, whereas the other three types of clasp revealed a significant decrease in the force required for removal during the test procedures (repeated analysis of variance P < 0.001). The results suggest that the cast titanium-nickel clasp may be suitable in removable prosthodontic constructions because of its significantly less permanent deformation during service. This report also discusses clinical applicability and some current problems with this new application.

Short stature due to growth hormone deficiency associated with Cushing's disease and ulcerative colitis.

We report a rare case of Cushing's disease associated with ulcerative colitis in a patient primarily treated with growth hormone due to short stature. At the age of fifteen years, the patient had a short stature due to GHD and was treated with the extracted GH for a short period. At the age of twenty-one years, his body weight gradually increased and, based on the results of several tests, he was diagnosed with Cushing's disease and GHD was observed in our patient. The excess secretion attenuation of pituitary hormones with reduced secretion periods as well as the relation between ulcerative colitis and elevated plasma cortisol concentrations is briefly discussed in this paper.

A case of myocarditis associated with IDDM.

We report a case of diabetic ketoacidosis (DKA) complicated by acute myocarditis, which was confirmed by cardiac biopsy. A 26-year-old man was hospitalized with severe DKA. On admission, nonspecific ST-T change was noted on the electrocardiogram (ECG). The patient's levels of creatine phosphokinase (CPK) and glutamic oxaloacetic transaminase were slightly elevated, but he did not complain of chest discomfort or symptoms of heart disease. On the first day after admission, ST-T elevation was noted on ECG during treatment of DKA. By cardiac angiography and cardiac biopsy, coronary heart disease was ruled out and postmyocarditic change was histologically confirmed. An episode of upper respiratory viral infection before the onset of acute diabetes suggested that the patient suffered from viral-induced myocarditis and consequent development of IDDM. This possibility was confirmed by the clinical course of ECG change, with elevated CPK and lactate dehydrogenase and a slightly elevated antibody titer for echovirus.

Changes in lipid peroxidation and free radical scavengers in the brain of hyper- and hypothyroid aged rats.

To determine how lipid peroxides and free radical scavengers are changed in the brain of hyper- or hypothyroid rats, we examined the behavior of lipid peroxide and free radical scavengers in the cerebral cortex of aged (1.5 years old) rats that had been made hyper- or hypothyroid by the administration of thyroxine or methimazol for 4 weeks. Concentrations of catalase, Mn-superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were increased in hyperthyroid rats compared with euthyroid rats. Concentrations of total SOD, Cu,Zn-SOD and GSH-PX were increased but that of Mn-SOD was decreased in hypothyroid animals. There were no differences among hyperthyroid, hypothyroid and euthyroid rats in the levels of coenzymes 9 or 10. The concentration of lipid peroxides, determined indirectly by the measurement of thiobarbituric acid reactants, was decreased in hyperthyroid rats but not in hypothyroid rats when compared with euthyroid animals. These findings suggest that free radicals and lipid peroxides are scavenged to compensate for the changes induced by hyper- or hypothyroidism.