Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

Histiocytic sarcoma of the palate: a case report.

Histiocytic sarcoma is a malignant proliferation of cells that exhibit morphological and immunophenotypic features of mature histiocytes. Owing to its rarity, its clinical features and standard treatment have not yet been established. This report describes a case of histiocytic sarcoma of the palate that developed in a 76-year-old man, the first report of an intraoral histiocytic sarcoma. An extended resection was performed; however, establishing the excision line was extremely difficult because assessing the tumour boundary on imaging was challenging and the tumour underwent dynamic gross morphological changes following biopsy. Complete resection is required to obtain a favourable prognosis for high-grade tumours with indistinct borders. In this case, an intraoperative rapid examination with frozen section analysis was performed along the planned excision line to completely resect the tumours exhibiting such behaviour. At 28 months postoperatively, the patient demonstrated no recurrence or metastasis; however, he is under careful monitoring.

Endoscope-assisted greater neurovascular palatal bundle release in cleft palatoplasty.

Performing surgery in the oral cavity is difficult because of the limited view of the surgical field. Intraoral surgery for infantile oral disorders, such as cleft palate, is even more challenging. Endoscopy provides a minimally invasive approach and clear surgical view in surgeries with a constrained field of view. To date, very few reports have described endoscope-assisted palate surgery for children with cleft palate. At the authors' institution, endoscopes have been used in primary palatoplasty using the double-opposing Z-plasty technique. A novel endoscope-assisted procedure is described herein, in which a dissection around the greater palatine neurovascular bundle is used to obtain tension-free closure of the palatal cleft. With this technique, it was possible to minimize the application of additional von Langenbeck-type relaxation incisions, which were previously introduced in most of our cases; the relaxation incision was successfully circumvented in 42.3% of cases. This led to lesser surgical interference, which possibly resulted in favourable palatal development. It was also found that the endoscopic procedure did not increase the operation time or blood loss when compared to those patients who underwent the non-endoscopic procedure. It is concluded that endoscopic guidance is quite useful in primary palatoplasty procedures with a constricted surgical view.

Phase I study on human monoclonal antibody against cytomegalovirus: pharmacokinetics and immunogenicity.

MAb C23, a human immunoglobulin G1 (IgG1) monoclonal antibody (MAb) against cytomegalovirus, was administered to 20 healthy volunteers. Sixteen of them received a single infusion of a dose ranging from 5 to 80 mg. The plasma clearance curves fit a two-compartment model, with half-lives of 31.0 +/- 23.6 h in the diffusion phase and 24.2 +/- 5.8 days in the equilibration phase. The plasma after administration had the virus neutralization activities that were equivalent to the plasma MAb C23 levels. The remaining four subjects, who received three infusions of 60, 20, and 20 mg at 1-week intervals, showed pharmacokinetics that were very consistent with those of the single infusion. No antibody response against MAb C23 was observed in any of the subjects at any time, when monitored for approximately 60 days after the single infusion or the third infusion of the three repeated doses. None of the 20 subjects showed any treatment-related clinical signs or changes. These results suggest that a human IgG MAb has the same pharmacokinetic characteristics as those of natural human serum IgG, and that it is not immunogenetic and is safe in humans.

Z-335, a new thromboxane A(2) receptor antagonist, prevents arterial thrombosis induced by ferric chloride in rats.

We examined the antithrombotic effect of Z-335 ((+/-)-sodium [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate monohydrate), an orally active thromboxane A(2) receptor (TP-receptor) antagonist that ameliorates experimental gangrene, using a rat arterial thrombosis model. The thrombi were induced by topical application of 50% ferric chloride solution to the rats abdominal artery. Z-335 (0.3-3 mg/kg, p.o.) inhibited thrombus formation in a dose-dependent manner. The antithrombotic effect of Z-335 (1 and 3 mg/kg, p.o.) was almost equivalent with that of cilostazol (100 mg/kg, p.o.), a selective phosphodiesterase type III inhibitor. The effect of Z-335 (3 mg/kg, p.o.), but not cilostazol, persisted for 16 h. Z-335, but not cilostazol, inhibited platelet aggregation induced by U-46619 (a TP-receptor agonist, 9, 11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F(2alpha)) for 16 h in rat whole blood. Histopathological examination also revealed that Z-335 prevented ferric chloride-induced thrombus formation. These results suggest that Z-335 may prevent ferric chloride-induced arterial thrombosis through its antiplatelet action by blocking TP-receptor activation.

Antiplatelet effect of Z-335, a new orally active and long-lasting thromboxane receptor antagonist.

We investigated the pharmacological characteristics of Z-335 ((+/-)-sodium[2-[4-(chlorophenylsulfonylaminomethyl)indan-5-yl]ace tate monohydrate), a new indan derivative. Z-335 inhibited the specific binding of [3H]SQ-29548 to human platelets and guinea pig platelet membranes. The IC50 values of Z-335 for human platelets and guinea pig platelet membranes were 29.9 +/- 3.1 nM with a slope of 1.09 +/- 0.05 and 32.5 +/- 1.7 nM with a slope of 1.07 +/- 0.02, respectively. Z-335 inhibited thromboxane A2 receptor-mediated human and guinea pig platelet aggregation in vitro and oral administration of this drug to guinea pigs inhibited U-46619- and collagen-induced platelet aggregation for 24 h. Z-335 dose-dependently prevented the occurrence of U-46619-induced pulmonary thromboembolism in mice and the protective effect of this drug (0.3 and 3 mg/kg, p.o.) lasted for 24 h. These results strongly suggest that Z-335 is a potent, orally active and long-lasting thromboxane A2 receptor antagonist, which may be useful as an antiplatelet drug.

Pharmacodynamic analysis of steroid 5alpha-reductase inhibitory actions of Z-350 in rat prostate.

The pharmacodynamics of (S)-4-[3-[4-[1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy]benzoyl]indole-1-yl] butyric acid hydrochloride (Z-350), which has alpha(1)-adrenoceptor antagonistic and steroid 5alpha-reductase inhibitory effects, were investigated in rats. The disposition of Z-350 was a function of linear kinetics at doses from 1 to 30 mg/kg; the bioavailability was calculated to be 65.2%. The inhibition of 5alpha-reductase was dependent on the concentration of Z-350 in plasma and in the prostate. Analysis of the relationship between the concentration in the prostate and the inhibition seen after a single oral administration showed that the Hill constant was almost 1.0 and EC(50)(n(H)) was 47.4 ng/g of tissue; these parameters did not change after multiple administration. Z-350 inhibited 5alpha-reductase 1 h after oral administration at a dose of 3 mg/kg; maximum inhibition was observed after 2-4 h, and the inhibition (%) was maintained for 24 h after oral administration.

A new thromboxane receptor antagonist, Z-335, ameliorates experimental thrombosis without prolonging the rat tail bleeding time.

We investigated the antithrombotic activity of Z-335, a new thromboxane A2 receptor antagonist, using experimental thrombosis models, and also tested its effect on the rat tail bleeding time. Z-335 (0.1, 0.3, and 1 mg/kg, p.o.) dose-dependently prevented the occurrence of arachidonic acid-induced pulmonary thromboembolism in mice. During photochemically induced thrombosis in the femoral artery of guinea pigs, Z-335 (0.3, 1, and 3 mg/kg, i.v.) dose-dependently prolonged the time required to form thrombi. Moreover, Z-335 (10 mg/kg/day, p.o.) strongly suppressed lauric acid-induced hind limb injury in rats. Z-335 (0.3, 3, 30, and 300 mg/kg, p.o.) did not prolong the tail bleeding time in rats. These results strongly suggest that Z-335 ameliorates experimental thrombosis without prolonging the rat tail bleeding time, and may therefore be a useful antithrombotic drug.

Heart with circulatory failure secretes and processes atrial natriuretic peptide in a manner different from normal heart.

The role of catecholamine in atrial natriuretic peptide (ANP) secretion and its secretory mechanism in normal humans is not well defined; therefore, we studied the relationship among ANP, catecholamine, and atrial pressures in 25 patients without cardiovascular disease and in 35 patients with chronic congestive heart failure (CHF, 20 in mitral valve disease and 15 in dilated cardiomyopathy). In patients without cardiovascular disease, right atrial pressure at rest showed a positive correlation (r = 0.80, p less than 0.001) with ANP concentration, whereas left atrial pressure did not. The relation narrowed (r = 0.82) when the bicycle ergometer exercise in the supine position was conducted. Neither adrenalin nor noradrenalin significantly correlated with ANP concentration. In patients with mitral valve disease and dilated cardiomyopathy, the significant relations (r = 0.56 p less than 0.001, r = 0.85 p less than 0.001, respectively) between left atrial pressures and ANP concentrations at rest were observed, and following exercise, induced more significant relations. Right atrial pressures did not correlate positively with ANP concentrations. The increments of ANP concentrations induced by exercise load were markedly reduced compared with those of patients without cardiovascular disease. Although concentrations of both noradrenalin and adrenalin in patients with mitral valve disease and dilated cardiomyopathy at rest were much higher than those without cardiovascular disease, only noradrenalin had a highly positive correlation with ANP concentrations (r = 0.88 p less than 0.001, r = 0.78 p less than 0.001, respectively). Furthermore, the circulating ANP molecular weight forms in all patients studied were analyzed by gel chromatography coupled with radioimmunoassay.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantification of infarct size by thallium-201 single-photon emission computed tomography using the unfolded map method. Comparison with QRS score and angiographic infarct size at 4 weeks after infarction.

A new technique of data processing, the unfolded map method, was used with thallium-201 single-photon emission computed tomography to quantify infarct size in 35 patients with single-vessel disease at 4 weeks after their first myocardial infarction (24 anterior and 11 inferior infarcts), and the results were compared with those obtained by electrocardiography and contrast left ventriculography. The myocardial borders and the infarcted region were defined using the threshold technique and a cutoff value of 55%. Count profile data for each short-axis slice were unfolded zonally into single planes with the same ratio, and their areas were calculated from the slice thickness and radius. Thus, the size of the unfolded map represented the actual left ventricular myocardial area Infarct size was quantitated from the ratio of pixels in the infarcted region to those in the whole map, and the ratio itself was used as the percent infarct size. Although a defect 1 cm in diameter (0.8 cm2) could not be detected in a phantom study, defects > or = 2 cm in diameter (> or = 3.1 cm2) could be measured satisfactorily. The infarct size and percent infarct size determined by the unfolded map method correlated well with the QRS score (r = 0.841 and r = 0.838), the percentage of abnormally contracting segments on left ventriculography (r = 0.835 and r = 0.877), and the ejection fraction (r = -0.835 and r = 0.856). These data indicate that the unfolded map method provides adequate quantification of infarct size, even in the chronic phase, without complicated data processing.

Ultrastructural study of a cerebral gangliocytoma.

A pure cerebral gangliocytoma leaving no sign or symptom of recurrence after surgical removal is reported, with special reference to its CT scan and the ultrastructural findings. Unusual, large, dense bodies having the size of 800-1200 m mu and radiating from a central core were identified on the ultrastructural study. Microcystic formations might have been produced by active secretory granules containing dense core vesicles. The literature concerning the dense core vesicle of ganglion cell tumors is reviewed.

Chronic administration of citalopram inhibited El mouse convulsions and decreased monoamine oxidase-A activity.

Serotonin (5-HT) is thought to play an important role in the seizures of El mice because the seizure threshold of El mice correlates with the 5-HT concentration in the central nervous system. In this study, the anticonvulsant effect of a 5-HT reuptake blocker, citalopram, was evaluated behaviorally and biochemically. El mouse convulsions were inhibited by chronic administration of citalopram (80 mg/kg/day, p.o. for 2 weeks), but were not inhibited by acute administration of citalopram (80 mg/kg, i.p., 2 h after single injection). Both chronic and acute administration of citalopram decreased the concentration of 5-hydroxyindolacetic acid in the brain, whereas the concentration of 5-HT was not changed by treatment with citalopram. Tryptophan hydroxylase activity was not different between the citalopram and control groups, although the monoamine oxydase-A activity was lowered by chronic administration of citalopram. These findings suggest that both acute and chronic administration of citalopram depresses the 5-HT turnover rate, however chronic administration is necessary to inhibit El mouse convulsions.

[Prognostic factors in acute subdural hematoma and the significance of serum FDP measurement].

Sixty-two cases of acute subdural hematoma were clinically analyzed with special reference to such prognostic factors as age, Glasgow Coma Scale (GCS) score on admission, pupillary signs, decerebration, and initial computed tomography (CT) findings. Intraparenchymal lesions demonstrated by CT were evaluated according to Yamaura's classification. In 19 cases, serum fibrin and fibrinogen degradation products (FDP) were measured at the time of admission. Emergency surgery was performed in 46 cases, and the remaining 16 patients were treated conservatively. The final outcome was judged according to the Glasgow Outcome Scale, and patients were divided into a "good outcome" group (good recovery or moderate disability) and a "poor outcome" group (severe disability, vegetative state, or death). In general, the outcomes proved to be unsatisfactory. Forty-four patients (71%) had a poor outcome, with 32/62 (52%) mortality, and only 18 (29%) had a good outcome. The clinical factors associated with a poor outcome were age over 64 years, a GCS score on admission of less than 7, decerebration, and absence of pupillary reaction to light. Initial CT scans showed brain damage in 46 patients (74%), 39 (85%) of whom had a poor outcome. This indicates that the outcome was significantly related to brain injury complicating the acute subdural hematoma. A high serum FDP level was similarly related to a poor outcome, which suggests that the serum FDP level reflects the degree of both primary and secondary brain injury. Thus, measurement of serum FDP may be valuable both in assessing clinical status and in evaluating the extent of brain injury in acute subdural hematoma.

[Combined effects of micronomicin and latamoxefi in vitro synergistic activities].

In vitro synergistic activities of new aminoglycoside antibiotic micronomicin (MCR, Sagamicin) combined with oxacephem antibiotic latamoxef (LMOX, Siomarin) were investigated. These antibiotics exhibited synergistic activities at FIC index lower than 0.5 against 20.8%, 32.7% and 1.9% of clinical isolates of Pseudomonas aeruginosa (48 strains), Serratia marcescens (52 strains) and Escherichia coli (54 strains), respectively. Partial synergism (0.5 less than FIC index less than 1) was observed in 79.2%, 55.8% and 31.5% of the same microorganisms, too. Each bacteriostatic concentrations of MCR and LMOX showed synergistically bactericidal effects when the drugs were administered at the same time against P. aeruginosa BMH No. 1, S. marcescens F-3283 and E. coli GN2411-5.

[Inactivation of aminoglycoside antibiotics by clinically isolated Pseudomonas aeruginosa].

Minimal inhibitory concentrations (MIC) of micronomicin (MCR) and gentamicin (GM) against clinically isolated Pseudomonas aeruginosa F 4150 were 1.56 mcg/ml and 6.25 mcg/ml, respectively. Sisomicin, dibekacin, amikacin, netilmicin, tobramycin ribostamycin and kanamycin did not inhibit the strain at the concentrations less than 25 mcg/ml. Each aminoglycoside antibiotic was incubated in Tris-HCl buffer solutions (pH 7.8) containing cell free crude enzyme preparations obtained by sonic oscillation of intact cells of P. aeruginosa F 4150, coenzyme A and adenosine-5'-triphosphate. The residual activity at 3 hours of incubation at 37 degrees C was 88% for MCR and 33.6% for GM, while all of the other aminoglycoside antibiotics tested were completely inactivated under this condition.

[Combined effects of astromicin and human gamma-globulin prepared for intravenous use].

Combination therapy of antibiotics and human intravenous gamma immunoglobulin (IgG) prepared for intravenous use is widely applied to control severe infectious diseases. To evaluate the antimicrobial activity of astromicin (ASTM, Fortimicin), the combination effect of ASTM with IgG was investigated in vitro and in mice with experimental infection (i.p.) with Pseudomonas aeruginosa BMH No. 1. Sulfonated IgG (Venilon, VL), and plasmin-treated IgG (Venoglobulin, VG) were administered (i.v., 42 mg/kg) 90 minutes before the infection, and ASTM was administered (s.c.) 60 minutes after the infection. Polyethyleneglycol-treated IgG (Venoglobulin-I, VG-I) was administered (i.v., 42 mg/kg) 90 minutes before or 60 minutes after the infection. ED50 of ASTM alone and that of combination with VL were 31.0 mg/kg and 24.2 mg/kg, respectively. ED50 of ASTM alone and that of combination with VG were 38.9 mg/kg and 15.5 mg/kg, respectively (P less than 0.05). When VG-I was administered prophylactically, ED50 of ASTM alone and that of combination were 51.5 mg/kg and 13.6 mg/kg, respectively (P less than 0.05). When VG-I was administered simultaneously with ASTM at 60 minutes after the infection, ED50 of ASTM alone and that of combination were 28.5 mg/kg and 15.5 mg/kg, respectively (P less than 0.05). Prophylactic effect of VG-I in immunosuppressed mice treated with cyclophosphamide (250 mg/kg, i.p., 4 days before infection) was also examined. ED50 of ASTM alone and that of combination were 126.1 mg/kg and 46.1 mg/kg, respectively (P less than 0.05). VG-I also enhanced in vitro synergistic bactericidal activity of ASTM and fresh mouse serum.

[The pharmacokinetic studies on astromicin in rats. Intramuscular, intravenous or drip intravenous administration].

Absorption, tissue distribution and excretion of astromicin (ASTM) were studied in rats after intramuscular (i.m.), intravenous (i.v.) or drip intravenous (d.i.v.; for 15, 30 min. or 60 min.) administration at a dose of 20 mg/kg. The pharmacokinetic studies of ASTM were carried out using one-compartment open model (i.m.) or two-compartment open model (i.v. and d.i.v.). The peak values of ASTM observed in serum were 48.6 micrograms/ml (i.m.), 255.3 micrograms/ml (i.v.), 57.5 micrograms/ml (15 min. d.i.v.), 45.9 micrograms/ml (30 min. d.i.v.) and 39.1 micrograms/ml (60 min. d.i.v.). The pharmacokinetic parameters of ASTM after 15 min. d.i.v. administration were calculated as follows: Kel 0.110 min-1, T1/2 21.4 min., Vd beta 0.310 L/kg, Tmax 15.0 min., Cmax 58.6 micrograms/ml, AUC 1,991 micrograms X min/ml. ASTM was rapidly distributed into the kidneys and lungs. The peak values of ASTM in the kidneys were 156.8 micrograms/g (i.m.), 185.2 micrograms/g (i.v.), 132.9 micrograms/g (15 min. d.i.v.), 135.3 micrograms/g (30 min. d.i.v.) and 117.3 micrograms/g (60 min. d.i.v.). Urinary recovery rates of ASTM amounted to 85.5% (i.m.), 99.5% (i.v.) or 87.9% (30 min. d.i.v.). After i.m. or 30 min. d.i.v. administration of ASTM, no active metabolite was found in urine of rats.

[Pharmacokinetic studies on micronomicin in rats. Comparison of intramuscular and drip intravenous administration models].

Absorption, tissue distribution and excretion of micronomicin (MCR) were studied in rats after intramuscular or 30 minutes drip intravenous administration (10 mg/kg). Serum levels of MCR were measured by bioassay, enzyme immunoassay and high pressure liquid chromatography. The pharmacokinetic studies of MCR after intramuscular or drip intravenous administration were carried out using one-compartment open model or two-compartment open model, respectively. Among 3 assay methods, similar pharmacokinetic parameters of MCR were obtained. In the simulation of serum levels of MCR, the differences between the measured and calculated serum levels after intramuscular or drip intravenous administration were less than 19% of the former levels. After intramuscular or drip intravenous administration of MCR, similar changes of the organ (kidneys, lungs, spleen and liver) levels were observed. Urinary recovery rates of MCR amounted to 82.3% or 91.6% by 24 hours after intramuscular or drip intravenous administration, respectively. After intramuscular or drip intravenous administration of MCR, no metabolites were found in urine of rats.

[On the surgical treatment of cerebellar infarction (author's transl)].

Recently we have experienced two cases of acute uncomplicated cerebellar infarction which had been surgically treated. Onset of the disease in both cases was an attack of vertigo with nausea and vomiting, followed by the signs of an expanding lesion in the posterior fossa. There were thirty-one surgically treated cases and only six were fatal so far as we have reviewed cases reported in the literature. The clinical pictures of cerebellar vascular accident are typical in most cases and those of cerebellar infarction are similar to those of cerebellar hemorrhage. These two are frequently indistinguishable on the clinical as well as angiographic grounds, however, CT-scan may be of great value in the differential diagnosis. It is important to realize the cerebellar infarction is also a surgical lesion and not to spend valuable time in differentiating cerebellar infarction from cerebellar hemorrhage. Low mortality rate and low morbidity in cerebellar infarction adequately treated surgically confirm importance for early exploration.

[Ischemic cerebral symptoms after subarachnoid hemorrhage due to aneurysmal rupture (author's transl)].

Among 169 patients treated at our clinic during past six years there were twenty-four cases (14 per cent) in which cerebral ischemic symptoms gradually developed after full recovery from SAH due to aneurysmal rupture. Duration form the aneurysmal rupture to the onset of ischemic symptoms varied from four days to fourteen days (8 days on average). As the initial symptoms hemiparesis and disturbance of consciousness (18 and 14, respectively) were two major symptoms, and those who showed disturbance of consciousness had more grave prognosis than those with hemiparesis. There were no correlations between the initial symptoms and the sites of aneurysm, but the ICA cases had definitely poor prognosis among those who developed ischemic signs after SAH. Those who became symptomatic within 7 days after SAH had poorer prognosis than those who showed initial symptom more than 8 days after SAH. On angiograms which were done shortly after the onset of symptoms, severe and extensive vasospasm was noted in all cases but four in which degree of vasospasm was not so severe and extensive. Operative treatment, when done within 5 days after the onset of ischemic symptoms had poorer results than when done over 6 days. As a conclusion, it is necessary to watch for possible onset of ischemic symptoms, especially in ICA patients, when seen later than four days after SAH. If ischemic symptoms were present and progressive, the operative treatment should be postponed until clinical course turns uphill by intensive treatments.