S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial.

BACKGROUND: The ACTS-CC 02 trial demonstrated that S-1 plus oxaliplatin (SOX) was not superior to tegafur-uracil and leucovorin (UFT/LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) and subgroup analysis according to the pathological stage (TNM 7th edition) for treatment efficacy. PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, five cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2/day of S-1 on days 1-14, every 21 days, eight cycles). The primary endpoint was DFS and the patients' data were updated in February 2020. RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the final analysis. With a median follow-up time of 74.3 months, the 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group [stratified hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.76-1.11; P = 0.3973], and the 5-year OS rates were 78.3% and 79.1%, respectively (stratified HR 0.97; 95% CI 0.76-1.24; P = 0.8175). In the subgroup analysis, the 5-year OS rates in patients with T4N2b disease were 51.0% and 64.1% in the UFT/LV and SOX groups, respectively (HR 0.72; 95% CI 0.40-1.31). CONCLUSION: Our final analysis reconfirmed that SOX as adjuvant chemotherapy is not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer. The 5-year OS rate was similar in the UFT/LV and SOX groups.

Cardiac functional and structural alterations induced by endotoxin in rats: importance of platelet-activating factor.

OBJECTIVE: In this study, we evaluated the time course of the alterations in left ventricular (LV) dimensions, LV wall thickness, and LV systolic function in rats with endotoxemia by using echocardiography as well as myocardial histopathologic assessments. Our second goal was to examine whether pretreatment with a platelet-activating factor (PAF) antagonist would ameliorate the lipopolysaccharide (LPS)-induced cardiovascular collapse during the early phase. DESIGN: A prospective, controlled, in vivo animal laboratory study. SETTING: Research laboratory at a university. SUBJECTS: Male, Wistar rats (8-9 wks old; n = 83). INTERVENTIONS: In pentobarbital-anesthetized rats, the right carotid artery was cannulated to measure the arterial blood pressure and to sample blood. The right jugular vein also was catheterized for the administration of drugs. LPS (2 mg/kg) derived from Klebsiella pneumoniae or physiologic saline was administered in the presence or absence of pretreatment with TCV-309, a specific potent PAF antagonist. Echocardiographic studies were performed with an 8- to 13-MHz transducer. MEASUREMENTS AND MAIN RESULTS: LPS administration immediately induced progressive hypotension. The maximal hypotensive response was observed at 10 mins after LPS infusion with mean arterial pressure decreasing from 119 +/- 2 to 56 +/- 3 mm Hg (p < .001). LV end-diastolic internal dimensions decreased from 6.4 +/- 0.1 to 3.1 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced compared with control rats. LV end-systolic dimensions also decreased dramatically from 3.5 +/- 0.2 to 0.5 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced throughout the experiment. LV fractional shortening increased from 45 +/- 1% to 84 +/- 2% (p < .001) at 30 mins after LPS and remained elevated compared with control rats. LV wall thickness increased strikingly from 15 mins until 2 hrs after LPS infusion. Pathologic studies demonstrated marked congestion of capillaries and mild edema in the LV myocardium. The hematocrit increased after the administration of LPS. LPS markedly increased sympathetic tone as demonstrated by the elevation of plasma concentrations of epinephrine and norepinephrine. There was no elevation of concentrations of nitrite and nitrate. Pretreatment with TCV-309, a specific potent PAF antagonist, reduced LPS-induced hypotension and attenuated LV functional and structural changes. TCV-309 administration reduced the LPS-induced adrenergic activation and hemoconcentration. CONCLUSIONS: The hypotension that occurred during the initial phase of LPS-induced shock was accompanied by LV functional and structural alterations. The marked increase in LV wall thickness can be ascribed to the congestion of capillaries and edema in the LV myocardium. Pretreatment with a PAF antagonist reduced LPS-induced alterations. PAF may play a pivotal role during the initial phase of LPS-induced cardiovascular responses.

Antitumor promoting effect of an active component of Polyporus, ergosterol and related compounds on rat urinary bladder carcinogenesis in a short-term test with concanavalin A.

The effect of fractions from a water extract of Polyporus on bladder tumor promotion was examined using 5% sodium saccharin (SS) in a short-term test with concanavalin A (Con A) in Wistar rats. Rats were given N-butyl-N-(4-hydroxybutyl) nitrosamine (BHBN) in drinking water for one week, and then promoter alone or test samples (given orally) plus promoter was administered for 3 weeks. Treatment with the BuOH fraction isolated from the water extract showed a strong inhibitory effect against the promoter. It was found that the inhibitory effect of the BuOH fraction is due to the effect of ergosterol contained in the fraction. Treatment with ergosterol showed a strong inhibitory effect against 5% SS, 0.01% BHBN, 3% DL-tryptophan (Trp) or 2% butylated hydroxyanisole (BHA); ID50 was 1.4 microg/kg/d, 2.9 microg/kg/d, 11.6 microg/kg/d, and 11.7 microg/kg/d against SS, BHBN, Trp and BHA, respectively. We also examined the effect of steroids and related compounds. Squalene and vitamin D2 showed strong inhibitory effect against 5% SS-induced bladder tumor promotion. These results strongly suggest that ergosterol could provide significant protection against the promotion of bladder tumor induced by many types of promoters in the environment.

Shift in sodium chloride sources in past 10 years of salt reduction campaign in Japan.

Twenty four-hr total food duplicate samples were collected from nonsmoking house-wives (aged mostly 30 to 60 years) twice at a 10-year interval in winter seasons, once in around 1980 and then in around 1990 in 11 prefectures in Japan. In practice, 342 and 472 samples were obtained in the 1980 and 1990 studies, respectively. Sodium chloride (NaCl) intake via each food item was estimated from the weight of the item in the duplicate. The comparison of 1990 results with 1980 results showed that the total NaCl intake (i.e., NaCl intake via all food items) decreased after a 10-year campaign to lower salt intake. The NaCl/energy ratio however stayed essentially unchanged. Whereas NaCl intake via pickles decreased remarkably and that via miso paste [a fermentation product of soy bean, rice (or wheat) and salt] slightly, the decreases were counteracted by a substantial increase in NaCl intake via soy bean sauce. Meaning of this unexpected counteraction was discussed in relation to the difficulties in the campaign to lower salt intake.

Contribution from crossed and uncrossed brainstem structures to the brainstem auditory evoked potentials: a study in humans.

The neural generators of the brainstem auditory evoked potentials (BAEPs) in humans are not completely known. Attempts to identify the anatomical location of the neural generators of the human BAEP based on the results of studies in animals commonly used in auditory experimentation have been difficult because of the considerable anatomical differences between the ascending auditory pathways in humans and animals. The authors of this study compared recordings obtained from different locations on the lateral side of the brainstem in six patients undergoing microvascular decompression surgery for a cranial nerve disorder affecting the fifth cranial nerve (i.e., trigeminal neuralgia). Ipsilateral click stimulation evoked prominent responses from the caudal aspect of the pons up to the junction between the pons and the midbrain, but all components of the responses with latencies shorter than 8 msec had smaller amplitudes when recorded at more rostral locations. Components with latencies in the range of peak V elicited by contralateral click stimulation had their largest amplitudes when recorded from the lateral brainstem at the level of the fourth cranial nerve (thus, close to the inferior colliculus). Earlier components of the contralateral responses (latencies in the range of the latency of peak III) had their largest amplitudes when recorded from the caudal lateral brainstem. The results of this study indicate that the part of the uncrossed auditory pathway that is located rostral to the cochlear nucleus contributes little to the farfield potentials (i.e., BAEP), and it is doubtful whether the contralateral response that can be recorded at the level of the cochlear nucleus contributes noticeably to the BAEP.

Overview of effects of electrical stimulation on osteogenesis and alveolar bone.

One endpoint of periodontal therapy is to regenerate structure lost to periodontal disease. Periodontal regeneration requires both formation of a new connective tissue attachment to the tooth and formation of alveolar bone. Several procedural advances may support regeneration of the attachment, however, regeneration of alveolar bone does not occur consistently. Therefore, factors which stimulate bone repair are areas for research in periodontal reconstructive therapy. Effects of cytokines or growth factors on bone repair are examples of such areas. Another one is electrical stimulation which naturally occurs in bone, and as such bone may be particularly susceptible to electrical therapy. This overview describes the potential of electrical stimulation for bone regeneration and applications in alveolar and periodontal research.

Improvement of cisplatin toxicity and lethality by juzen-taiho-to in mice.

The effects of oral treatment with 1-, 5-, 10- and 20-fold the usual daily dose of Juzen-taiho-to on the nephrotoxicity, immunosuppression, hepatic toxicity and gastrointestinal toxicity caused by i.p. administration of 3.0 mg/kg cisplatin (CDDP) 9 times (on days 3, 4, 5, 6, 7, 8, 10, 11, and 12) were examined in ddY mice inoculated with sarcoma 180 (S-180) cells on day 1. The increase in blood urea nitrogen, serum creatinine, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminases and relative stomach weight and decrease in white blood cell count, platelet count, relative spleen and thymus weight, food intake and body weight caused by CDDP were inhibited to nearly the control levels without reducing the antitumor activity of CDDP against S-180 by the oral treatment with either 10-fold (1.7 g/kg) or 20-fold (3.4 g/kg) the usual daily dose of Juzen-taiho-to 12 times (on days 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, and 15). All the mice receiving 4.5, 6.0, 7.5, 9.0, and 12.0 mg/kg CDDP died by day 12, while treatment with 3.4 g/kg Juzen-taiho-to efficiently prolonged the survival time. These findings indicate that Juzen-taiho-to may provide protection against most clinical toxicity caused by CDDP, and Juzen-taiho-to may allow us to administer a much higher dose of CDDP in clinical therapy.

Protective effect of sodium L-malate, an active constituent isolated from Angelicae radix, on cis-diamminedichloroplatinum(II)-induced toxic side effect.

The effects of ingredients of Shi-Quan-Da-Bu-Tang (Juzen-taiho-to) on the nephrotoxicity and bone marrow toxicity caused by i.p. administration of 3 mg/kg cis-diamminedichloroplatinum (II) (CDDP) 9 times (on days 3, 4, 5, 6, 7, 8, 10, 11, 12) were examined in ddY mice s.c. inoculated with sarcoma 180 (S-180) cells on day 1. Angelicae Radix showed the strongest protective effect against the toxicity among the ingredients. The ED50 of a water extract of Angelicae Radix was 17.8 mg/kg for nephrotoxicity (indicated by an increase in blood urea nitrogen) and 59.4 mg/kg for bone marrow toxicity (indicated by a decrease in white blood cell count), when it was administered perorally (p.o.) on days, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15. The water extract did not exert any significant effect on the antitumor activity of CDDP. Bioassay-directed fractionation of the water extract resulted in isolation of a constituent having protective effects against the toxicity: sodium L-malate, C4H4Na2O5, was found to exhibit protective effects against both nephrotoxicity (ED50: 0.4 mg/kg, p.o.) and bone marrow toxicity (ED50: 1.8 mg/kg, p.o.), without reducing the antitumor activity of CDDP. These findings indicate that Angelicae Radix and its constituent sodium L-malate could provide significant protection against CDDP-induced nephrotoxicity and bone marrow toxicity without reducing the antitumor activity.

Effects of aging on amplitude-modulation following response.

Phase spectral analysis as developed by Fridman (1982) was used to detect amplitude-modulation following response (AMFR). The threshold of AMFR was determined with greater sensitivity and accuracy by phase spectral analysis than by visual analysis. Using this method, a modulation frequency (MF) of 80 Hz was found optimal for detecting AMFR in young children (ranging in age from 2 to 4 years) during sleep, for whom there is no advantage in recording 40-Hz steady-state responses. To determine the optimal MF for detecting AMFR during sleep in children less than 2 years of age and age limitation for using 80-Hz MAFR in objective audiometry, AMFR as a function of MF was investigated during sleep in 25 children with normal hearing ranging from 4 months to 15 years of age, and 10 normal hearing adults. The stimulus was a 1000 Hz, 50 dBnHL sinusoidally amplitude modulated tone with a modulation depth of 95%. MF was varied from 20 to 200 Hz in 20 Hz steps. Response was determined by phase spectral analysis and the S/N ratio calculated by spectral amplitude at the modulation frequency and noise level around the modulation frequency using fast Fourier transform. Phase spectral analysis showed AMFR at MF of 80 Hz to be the most stable and reliable in all children during sleep among MFs from 20 to 200 Hz. Spectral amplitude analysis demonstrated 80-Hz AMFR to have a high S/N ratio in all children.(ABSTRACT TRUNCATED AT 250 WORDS)

Detectability of amplitude-modulation following response at different carrier frequencies.

To assess the detectability of amplitude-modulation following response (AMFR) elicited at different carrier (CFs) and modulation frequencies (MFs) during sleep, as well as the usefulness of AMFR in evoked response audiometry, AMFR was examined in 10 adults with normal hearing while sleeping. The stimulus was a 50 dBnHL sinusoidally amplitude-modulated (SAM) tone with a modulation depth of 95%. The MF of the stimulus tone was varied from 20 to 120 Hz in 20 Hz steps and CFs were 500, 1000, 2000 and 4000 Hz. An SAM tone with a CF of 20,000 Hz was used for stimulation in 5 subjects to confirm that the response did not contain any artifact. Response was determined by phase spectral analysis. The component synchrony measure of AMFRs at MF of 40 Hz (40-Hz AMFR) was high at lower CFs, but 40-Hz AMFRs at higher CFs were unreliable. The detectability of 80-Hz AMFR was high for all CFs. It was confirmed that the response waveform was not contaminated by any electromagnetic artifact. Eighty-Hz AMFR detected by phase spectral analysis should thus be useful for predicting frequency-specific hearing thresholds during sleep.

Pure-tone threshold prediction by 80-Hz amplitude-modulation following response.

The usefulness of 80-Hz amplitude-modulation following response (AMFR) detected by phase spectral analysis to predict the hearing threshold during sleep was evaluated in 20 normal adults, 8 normal children and 37 children with hearing impairment. The onset effect of tonal stimulus on 80-Hz steady state response was studied in normal adults during sleep and a threshold of 80-Hz AMFR detected by phase spectral analysis was compared with that of ABR elicited by tone pips in children during sleep. Although 80-Hz AMFR is not appropriate for the assessment of hearing in adults, it appears useful for evaluating hearing in young children during sleep. Hearing prediction by 80-Hz AMFR appears to be more accurate than that by ABR elicited with tone pips. The onset effect of stimulus on 80-Hz AMFR with modulation depth of 95% was less than 80-Hz SSR evoked by clicks.

Clonal dental pulp cells (RDP4-1, RPC-C2A) synthesize and secrete osteopontin (SPP1, 2ar).

Dental pulp cells play an important role in maintaining dental mineralized tissue throughout life. Supplementary mineralization such as reparative dentin and pulp stone frequently occurs after primary dentin formation. Dental pulp cells are thought to be closely associated with such mineralization. We found that clonal rat dental pulp cells, RDP4-1 and RPC-C2A, produce and secrete osteopontin, but do not synthesize phosphophoryn which is a major noncollagenous protein found in dentin. The dental pulp osteopontin was highly phosphorylated and identified by thrombin susceptibility and immunoprecipitation with osteopontin/2ar antibody. Osteopontin synthesis markedly increased by 12-O-tetradecanoylphorbol-13-acetate (TPA) as observed in many osteoblastic cells. This study indicates that these cells can produce osteopontin as a major phosphoprotein and suggests that the synthesis of osteopontin could be used as a characteristic marker of dental pulp cells.

The effects of a high dose of ascorbate on ischemia-reperfusion-induced mitochondrial dysfunction in canine hearts.

The cardioprotective effects of a high dose of ascorbate on ischemia-reperfusion-induced myocardial damage were investigated using open chest anesthetized dogs. Two-hour occlusion of the left anterior descending coronary artery (LAD) induced mitochondrial dysfunction with a depletion of mitochondrial glutathione (GSH) concentration. Two-hour LAD occlusion followed by 1-h reperfusion worsened the ischemia-induced mitochondrial dysfunction together with a marked depletion of mitochondrial GSH concentration. Ascorbate reduced the mitochondrial dysfunction and prevented the depletion of mitochondrial GSH concentration after 2-h LAD occlusion and 1-h reperfusion. Activities of mitochondrial glutathione peroxidase and glutathione reductase did not change significantly in each group. Administration of ascorbate also prevented reperfusion arrhythmias without affecting blood pressure or heart rate. These results suggest that coronary reperfusion induces mitochondrial dysfunction and a depletion of mitochondrial GSH concentration, and that a high dose of ascorbate prevents reperfusion damage.

Mechanism of anti-inflammatory action of etodolac.

The effect of etodolac (CAS 41340-25-4) on the inflammatory reactions induced by histamine and bradykinin was compared with that of indomethacin and other nonsteroidal anti-inflammatory drugs. Etodolac (50 mg/kg p.o.), indomethacin (20 mg/kg p.o.), diclofenac Na (20 mg/kg p.o.) and acetylsalicylic acid (200 mg/kg p.o.) had no effect on the increase of vascular permeability induced by histamine or bradykinin and on passive cutaneous anaphylaxis in rats. Etodolac (5, 10 and 20 mg/kg p.o.) suppressed concanavalin A-induced paw edema in rats. Etodolac (10 mg/kg p.o.) and bromelain (10 mg/kg i.v.) significantly suppressed the heat-induced elevation of bradykinin in perfusates of rat paws, but indomethacin (20 mg/kg p.o.) and diclofenac Na (20 mg/kg p.o.) did not. Etodolac inhibited bradykinin-forming enzyme activity in a concentration-dependent manner (IC50 = 1.5 x 10[-4) mol/l). These results suggest that etodolac is a unique nonsteroidal anti-inflammatory drug which can inhibit bradykinin formation, unlike indomethacin or diclofenac Na.

Hemodynamic mechanisms of antianginal action of calcium channel blocker nisoldipine in dynamic exercise-induced angina.

To investigate the mechanism of antianginal action of the calcium channel blocker nisoldipine and to determine the reproducibility of the clinical and hemodynamic events induced by supine leg exercise, 30 patients with stable effort angina pectoris were studied. They were divided into two groups; one group of 19 patients received a single 10-mg dose of nisoldipine orally, and the other group of 11 patients received a single dose of placebo orally. Chest pain was induced in all of 30 patients during the control exercise test. After nisoldipine administration, chest pain was not induced in 13 of 19 patients and was of lessened severity in five patients with the same work load as those performing control exercise. ST segment at peak exercise showed less severe depression after nisoldipine. Systemic vascular resistance was reduced by 38% (p less than 0.001) at rest and 22% (p less than 0.001) at peak exercise, and coronary vascular resistance was reduced by 31% (p less than 0.01) at rest and 18% (p less than 0.01) at peak exercise. Pulmonary artery wedge pressure fell from 6 +/- 1 to 3 +/- 1 mm Hg (p less than 0.001) at rest and from 28 +/- 3 to 11 +/- 2 mm Hg (p less than 0.001) at peak exercise. Coronary sinus flow at rest and myocardial oxygen uptake both at rest and during exercise was not modified by nisoldipine. However, coronary sinus flow at peak exercise increased significantly from 219 +/- 24 to 249 +/- 31 ml/min (p less than 0.01) after nisoldipine, and myocardial oxygen uptake was not significantly changed despite decreased coronary vascular resistance. The clinical and hemodynamic events induced by the exercise during invasive studies (except pulmonary artery wedge pressure at rest) were reproducible after placebo administration. Our data demonstrate that increased coronary blood flow could be the major mechanism of the antianginal action of nisoldipine in supine leg exercise-induced angina.

Biosynthesis of leukotrienes in canine cerebral vasospasm.

We produced cerebral vasospasm in 29 dogs by the "two-hemorrhage" method of intracisternal injections, 2 days apart, of autogenous arterial blood. Leukotriene (LT) C4, LTD4, and LTE4 were purified from incubated basilar artery, medulla oblongata, hypothalamus, median eminence, and blood clot from around the basilar artery using reverse-phase high-performance liquid chromatography, and the amount of each LT was quantified separately by bioassay with guinea pig ileum. The biosynthetic capacity for total LTs was approximately three times higher in the hypothalamus and median eminence than in the basilar artery and medulla oblongata in the eight normal dogs. In the dogs with subarachnoid hemorrhage, the biosynthetic capacity was increased significantly both before and 2 hours after the second injection of blood on Day 2 and was normal on Day 7 in the basilar artery and medulla oblongata, whereas the biosynthetic capacity was decreased significantly 2 hours after the first and second injections of blood and was increased significantly on Day 7 in the hypothalamus and median eminence. In blood clot the biosynthetic capacity was increased continuously after the first injection of blood. Thus, the biosynthetic capacity for total LTs showed a time- and tissue-specific change after subarachnoid hemorrhage.