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.

Submucosal tumor appearance is a useful endoscopic predictor of early primary-site recurrence after definitive chemoradiotherapy for esophageal squamous cell carcinoma.

Chemoradiotherapy (CRT) for esophageal cancer is disadvantageous because of a high locoregional failure rate. Detecting early small recurrent cancers at the primary site is necessary for potential salvage treatment. However, most endoscopists are inexperienced and therefore, a role for surveillance endoscopy after complete remission (CR) has not been established. We retrospectively evaluated serial surveillance endoscopic images from patients eventually proved to have primary-site recurrence in order to identify useful endoscopic features for early diagnosis. From January 2000 to December 2004, 303 patients with esophageal squamous cell carcinoma underwent definitive CRT, and 133 of them achieved CR. The surveillance endoscopic images stored at intervals of 1-3 months for the 16 patients with recurrence only at the primary tumor site and the 61 patients with no recurrence were collected for reexamination. Among 133 patients who achieved CR, 16 (12%) developed only local recurrence at the primary site. Thirteen of the 16 primary-site recurrent tumors (81%) appeared as submucosal tumors (SMT), with the remaining appearing as erosions or mild strictures. Of biopsy-proven recurrences, 81% were preceded by newly developed lesions such as SMT, erosions, or mild strictures detected by earlier surveillance endoscopies. For all 77 patients achieving CR with no metastasis, 86% of the evolving SMT with negative biopsies were eventually confirmed as cancer at later endoscopies. Thirteen of the 21 evolving lesions were subsequently confirmed as recurrent cancer. Early primary-site recurrence of esophageal cancer after a complete response to CRT is detectable with frequent endoscopic surveillance. SMT appearance is a useful endoscopic sign of early recurrence, as well as a predictor of subsequent diagnosis of recurrence.

Photocatalytic degradation of gaseous perchloroethylene: products and pathway.

Batch photocatalytic degradation of 1000-ppm gaseous perchloroethylene (PCE) was conducted with UV irradiation such that nearly 100% was decomposed within 10 min. The main intermediate and final product were identified as trichloroacetylchloride (TCAC) and hydrogen chloride (HCl), respectively, and minor ones as dichloroacetic acid (DCAC), monochloroacetic acid (MCAC), carbon tetrachloride, chloroform, and phosgene. More than 90% of Cl- equivalent, i.e., the sum of the chlorine number in PCE, intermediates, and HCl, was compensated for during the time of PCE degradation; a result indicating that no other major chlorinated intermediates are present during the time of PCE degradation. In a similar experiment, 500 ppm of gaseous TCAC degraded into HCl within 3 h without producing DCAC or MCAC, where like PCE, more than 90% of Cl- equivalent, i.e., the sum of the chlorine number in TCAC and HCl, was compensated for during time of TCAC degradation. Accordingly, gaseous PCE is concluded to predominantly follow a degradation pathway of PCE --> TCAC --> HCl.

[Quick radioimmunoassay for plasma immunoreactive gastrin--application for localizing occult gastrinoma(s) during operation].

A rapid method for determining gastrin, quick gastrin, has been developed. Separation/washing procedure has been improved and can be completed within three minutes. It required only 48 minutes for the assay of 22 blood samples. Quick gastrin is a RIA that uses magnetic particles. On magnetic particles, a goat anti-rabbit IgG antibody is bound covalently. An anti-human gastrin rabbit antibody is bound to an anti-rabbit IgG antibody. Assay is started by adding the magnetic particles to a mixture of sample and 125I-gastrin. Following 30 minute incubation at 37 degrees C, the particles are sedimented in a magnetic field and washed. The gastrin content of the sample is then quantitated by counting radioactivity of the particles. Incomplete equilibration of antigen-antibody reaction is corrected using standard solution prepared from charcoal treated plasma. The immunoreactive gastrin values by quick gastrin correlated well with those by a commercial assay kit (Gammadab RIA kit; y = 1.01 x +4.3, r = 0.99). When compared to a reported conventional rapid assay, quick gastrin is easier and more accurate. Quick gastrin is sensitive enough to use for intra-operative determination of gastrin. We applied quick gastrin to the samples obtained from intra-operative secretin test in a gastrinoma patient. Twofold increases in gastrin after injection of secretin clearly indicated the existence of occult gastrinomas in her pancreas. When gastrin was assayed with the conventional rapid method, the increase in gastrin was less and did not reach the criteria for existence of gastrinoma.

[A case of subacute sclerosing panencephalitis treated with intraventricular interferon--the side effects of interferon-alpha to the central nervous system].

A patient with subacute sclerosing panencephalitis (SSPE) was treated with an intraventricular alpha interferon (IFN-alpha) through an Ommaya reservoir. A 17-year-old boy, who had a history of measles exposure at age 1, showed forgetfulness, difficulties in calculation, reading and writing. Two months later he developed generalized convulsions and myoclonic spasms. He was admitted to the National Saigata Hospital in May 20, 1992. On admission, anti-measles antibody titer in the CSF was 1:16 by complement-fixation method. His EEG revealed a periodic synchronous discharge. Therefore, the diagnosis of SSPE was confirmed. An Ommaya reservoir was implanted on July 7, 1992, and an intraventricular administration of INF-alpha was begun after two weeks. The dose of INF-alpha was gradually increased from 1.0 x 10(6) IU/m2 to 2.0 x 10(6) IU/m2 twice a week. Fever, vomiting and anorexia were developed when the INF-alpha injection was first started. When he received a total dose of 8.0 x 10(6) IU, he became bed ridden for remarkable lethargy. The lethargy was continued for about 10 days despite the therapy was interrupted, and then he gradually became alert. The frequency of myoclonus became more frequent and mentality got worse, so the treatment with INF-alpha was tried again in decreasing the dose to 1.0 x 10(6) IU/m2 twice a week. However, be became drowsy again after he received a total of 7.5 x 10(6) IU. With intramuscular or intravenous administrations of the high doses of INF-alpha (> or = 1.0 x 10(7) IU), significant neurological abnormalities were reported to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and structure of a vesicular assembly of dialkylammonium-type amphiphile carrying L-3-(3-N-ethylcarbazolyl)alanine.

A novel unnatural amino acid, L-3-(3-N-ethylcarbazolyl)alanine, was synthesized and used for synthesis of a chiral dialkylammonium-type amphiphile. The synthetic amphiphile formed a vesicular assembly in aqueous dispersion showing gel-liquid crystalline phase transition around 25 °C. The bilayer membrane composed of the amphiphile was nearly free from excimer as evidenced by fluorescence spectroscopy.

[Marinesco-Sjögren syndrome--report of two patients in a family with muscle CT study].

Two patients with Marinesco-Sjögren syndrome in a family were characterized by autosomal recessive inheritance, congenital cataract, cerebellar ataxia, mental retardation, short stature and variable skeletal abnormalities. Muscle biopsy specimens showed replacement of muscle fibers by fat and fibrous tissue, a marked variation of fiber size and a rimmed vacuole formation. Nerve biopsy specimens showed a reduced number of myelinated nerve fibers in the sural nerves. Muscle CT revealed atrophy of the quadriceps femoris, semitendinosus, gastrocnemius and soleus muscles. Accordingly, extensor muscles in the thighs were more preferentially involved than flexor muscles in the legs.

Effects of lipid structure on energy transfer from carbazolyl to anthryl groups in a lipid bilayer.

Two types of chromophoric amphiphiles were synthesized: one of them possesses a molecular structure of N,N-dialkyl aromatic amino acid (5X18 type, where X is A or Cz), and the other alpha,gamma-dialkylglutamate connected to aromatic amino acid (mXG12 type, where m is an integer). 5-N-Ethylcarbazolyl and 9-anthryl groups were chosen as the chromophore, and introduced to each amino acid derivative. All the amphiphiles formed assembly showing gel-liquid crystalline phase transition. The phase-transition temperature of the assembly composed of mXG12-type amphiphile was higher than that of 5X18-type amphiphile. Absorption and CD spectra of 6-(trimethylammonium)hexanoyl-L-3-(5-N-ethylcarbazolyl) alanine N,N-dioctadecylamide bromide (5Cz18) in the assembly indicated the absence of strong ground-state interactions between the carbazolyl groups, while those of 6-(trimethylammonium)hexanoyl-L-3-(5-N-ethylcarbazolyl)alanyl-L-gl utamic acid alpha,gamma-didodecyl ester (5CzG12) or 11-(trimethylammonium)undecanoyl-L-3-(5-N-ethylcarbazolyl)al anyl-L-glutamic acid alpha,gamma-didodecyl ester (10CzG12) indicated the ground-state interactions based on dimer or higher aggregates. Fluorescence spectra of 5Cz18 showed very weak excimer emission, while excimer and/or excited dimer or higher aggregates were observed in the assembly of 5CzG12 or 10CzG12. Similar results were obtained for amphiphiles (mAG12) with anthryl and hydroxyethyldimethylammonium groups in places respectively of carbazolyl and trimethylammonium groups of 5CzG12 and 10CzG12. Taking these results together into consideration, the molecular packing of mXG12 in the assembly should be tighter than that of 5X18. In the binary assembly of 6-(trimethylammonium)hexanoyl-L-3-(9-anthryl) alanine N,N-dioctadecylamide bromide (5A18)/5Cz18 (1/99 mol/mol), about 60% of photoenergy absorbed by the carbazolyl groups was transferred to the anthryl groups, indicating an efficient energy migration along the two-dimensional array of carbazolyl chromophores of 5Cz18. On the other hand, in the mCzG12/mAG12 binary assembly, the energy-transfer efficiency was much lower due to the formation of dimer or the higher aggregates acting as energy-dissipating sites.

Single photon emission computed tomography in children with idiopathic seizures.

Single photon emission computed tomography (SPECT) with N-isopropyl-p[123I]-iodoamphetamine (IMP), X-ray computed tomography (X-CT), and magnetic resonance imaging (MRI) were performed in 20 children with idiopathic seizures. In children with idiopathic seizures, SPECT could detect the abnormal sites at the highest rate (45%) compared with CT (10%) and MRI (12%), but the abnormal sites on SPECT correlated poorly with the foci on electroencephalograph (EEG). Idiopathic epilepsy with hypoperfusion on SPECT was refractory to treatment and was frequently associated with mental and/or developmental retardation. Perfusion defects on SPECT scans probably affect the development and maturation of the brain in children.

Infantile osteopetrosis complicating neuronal ceroid lipofuscinosis.

An autopsy case of infantile osteopetrosis complicating neuronal ceroid-lipofuscinosis is reported. Autopsy revealed generalized sclerosis and thickening of cortical and spongy bones, formation of mineralized cartilagenous tissues, and narrowing of the marrow cavities associated with decreased hematopoietic cell components. Around the thickened bone trabecles, osteoclasts lacked a ruffled border and clear zone along the cell membrane facing the bone matrix surface. The brain was markedly atrophic with neuronal cell loss and focal gliosis, and the remaining neuronal cells accumulated brown granular pigments, which were confirmed histochemically and electron-microscopically to be ceroid and lipofuscin. In the cerebral medulla, the development of myelin sheaths was extremely poor. Also, the occurrence of Lex type glycolipids and GM3 and the apparent absence of cerebroside and cerebroside sulfate were proved by biochemical analysis, suggesting that the brain was still in a stage of embryonic development or still in the process of differentiation. Except for one suggestive case, this is the first case of complicating neuronal ceroid-lipofuscinosis in infantile osteopetrosis.

[123I-IMP single photon emission computed tomography (SPECT) study in childhood epilepsy].

N-isopropyl-p[123I]-iodoamphetamine (IMP) single photon emission computed tomography (SPECT), X-ray computed tomography (X-CT) and magnetic resonance imaging (MRI) were performed in 18 children with idiopathic seizures. In children with idiopathic seizures SPECT identified abnormal lesions in the highest rate (50%) compared with X-CT (11%) and MRI (13%), but the findings of SPECT poorly correlated with the foci on electroencephalography (EEG). Idiopathic epilepsy with abnormal uptake on SPECT was refractory to medical treatments and frequently associated with mental and/or developmental retardation. Perfusion defects identified on SPECT probably influenced the development of the brains in children. IMP SPECT is useful in the diagnosis and medical treatment in children with seizures.

Gammaglobulin therapy in a case of chronic relapsing dysimmune polyneuropathy.

A boy with chronic relapsing dysimmune polyneuropathy was treated with intravenous gammaglobulin injections for the fourth and fifth episodes, and showed rapid clinical improvement compared with in the three previous episodes, when he was treated by high dose steroid administration.

Clinical improvement of adrenoleukodystrophy following intravenous gammaglobulin therapy.

A patient with adrenoleukodystrophy was successfully treated by means of intravenous gammaglobulin injections. The clinical symptoms, especially visual loss, were apparently relieved and no neurological deterioration was observed during a 18-month period following the start of the gammaglobulin treatment.

Vascular endothelial cell injury and platelet embolism in Duchenne muscular dystrophy at the preclinical stage.

Blood vessels in muscle biopsy specimens from 4 Duchenne muscular dystrophy (DMD) patients (including 3 at the preclinical stage) were examined by electron microscopy and compared with those in non-diagnostic biopsy specimens from age-matched controls and cases of other childhood neuromuscular disorders. The most striking feature was the blister-like swelling of vascular endothelial cells in the biopsied muscle specimens from the 3 preclinical stage DMD patients, which was observed in 23-39% of the small blood vessels examined. Other noticeable features in the preclinical DMD patients were: (1) replication of the basement membrane, there being more than 3 layers in 30% of the capillaries; (2) many degenerating and regenerating capillaries; and (3) platelet adhesion and aggregation in small blood vessels including small arteries and veins. Morphometric analysis showed that the capillary and endothelial cell areas were much greater in the preclinical DMD patients than in the controls or the cases of the other neuromuscular disorders. These phenomena strongly suggest an as yet undetermined process in blood vessels in preclinical DMD.

Creatine kinase brain isoenzyme in infantile osteopetrosis.

A 14-month-old girl with infantile osteopetrosis had hematologic and neurologic complications with severe brain atrophy. Although serum contained high creatine kinase brain isoenzyme activity (CK-BB), CK-BB activity was not detected on repeated cerebrospinal fluid examinations. After frequent blood transfusions and steroid therapy, hematologic involvement improved gradually and disappeared finally at age 11 months; serum CK-BB tended to show a concomitant proportional increase in activity. A 111Indium chloride scan was performed at age 4 weeks when the patient had relatively low serum CK-BB activity. It indicated active extramedullary hematopoiesis in the liver and spleen. The second scan was performed at age 12 months when she had high serum CK-BB activity and indicated active medullary hematopoiesis in the cranium. The tests disclosed that the elevated serum CK-BB activity was the result of bone marrow serum leakage, and not leakage from brain tissue. This finding may be a good marker of medullary hematopoietic activity in patients with osteopetrosis. Meanwhile, biopsied sural nerve revealed storage of cellular debris, including myelin figures in the Schwann cells, which suggested increased degradation process in the cells or lysosomal enzyme deficiency.