BRAF V600E mutant oligodendroglioma‐like tumors with chromosomal instability in adolescents and young adults

We performed genome‐wide methylation analysis on 136 pediatric low‐grade gliomas, identifying a unique cluster consisting of three tumors with oligodendroglioma‐like histology, BRAF p.V600E mutations and recurrent whole chromosome gains of 7 and loss of 10. Morphologically, all showed similar features, including a diffusely infiltrative glioma composed of round nuclei with perinuclear halos, a chicken‐wire pattern of branching capillaries and microcalcification. None showed astrocytic features or characteristics suggestive of high‐grade tumors including necrosis or mitotic figures. All tumors harbored multiple chromosomal copy number abnormalities (>10 chromosomes altered), but none showed 1p/19q co‐deletion or IDH1 p.R132H mutation. Hierarchical clustering and t‐stochastic neighbor embedding analyses from DNA methylation data cluster them more closely to previously described pediatric‐type low‐grade gliomas and separate from adult gliomas. These tumors exhibit distinct clinical features; they are temporal lobe lesions occurring in adolescents and young adults with a prolonged history of seizures and all are alive with no recurrence (follow‐up 3.2 to 13.2 years). We encountered another young adult case with quite similar pathological appearance and molecular status except for TERT promoter mutation. Although the series is small, these may represent a new category of IDH wild‐type low‐grade gliomas which may be confused with “molecular GBM.” Further, they highlight the heterogeneity of IDH wild‐type gliomas and the relatively indolent behavior of “pediatric‐type” gliomas.     

Nonlinearity identified by neural network models inP CO 2 control system in humans

The nonlinearity included in the P_{CO 2} control system in humans is evaluated using the degree of nonlinearity based on a difference of residuals. An autoregressive moving average (ARMA) model and neural networks (linear and nonlinear) are employed to model the system, and three types of network (Jordan, Elman and fully interconnected) are compared. As the Jordan-type linear network cannot approximate respiratory data accurately, the other two types and the ARMA model are used for the evaluation of the nonlinearity. The results of the evaluation indicate that the linear assumption for the P_{CO 2} control system is invalid for three subjects out of seven. In particular, strong nonlinearity was observed for two subjects.     

Efficacy of a New 5-Fluorouracil Derivative, Bof-A2, in Advanced Non-Small Cell Lung Cancer a Multi-Center Phase Ii Study

Oral BOF-A2 (Emitefur), a new derivative of 5-fluorouracil (5-FU) containing both 1-ethoxymethyl-5-FU (EMFU), a masked form of 5-FU, and 3-cyano-2,6-dihydroxypyridine (CNDP), an inhibitor of 5-FU degradation, was administered to 71 non-small cell lung cancer (NSCLC) patients in a multi-center phase II study. The patients were scheduled to receive at least 2 courses of treatment, each consisting of 200 mg twice daily for 2 weeks followed by a 2-week rest period. Out of 62 evaluable patients, 11 (18%) responded (8 of 44 adeno- and 3 of 15 squamous cell carcinomas). Thirty-four patients showed no change and 17 progressive disease. The incidences of grade ≥ 2 hematologic toxicity were 5-8% for leukopenia, thrombocytopenia, and anemia. The incidences of non-hematologic toxicity of grade ≥ 2, such as anorexia, nausea/vomiting, and diarrhea, were close to 20% or lower.     

Significance of Serum Neuron-specific Enolase as a Predictor of Relapse of Small Cell Lung Cancer

We conducted a prospective study to evaluate the significanceof serum neuron-specific enolase (NSE) as a predictor of relapseof small cell lung cancer (SCLC). Patients entered into thestudy were drawn from those who had shown a complete or partialresponse to first-line chemotherapy with a concurrent declinein the NSE level to less than 10 ng/ml. When the serum NSE levelincreased to more than 15 ng/ml, the patient was restaged onthe basis of clinical, radiological, and bronchoscopic examinations.During the period from August 1988 to December 1990, 57 patientswith SCLC were enrolled and followed up until May 1992; Of thesepatients, 45 had clinical relapses, and 14 (31%) of them showeda clear elevation of the serum NSE level prior to the clinicalrecognition of relapse. Although one false-positive case wasnoted, this involved only a transient elevation of the NSE level.In patients who showed increased NSE levels, the relapses occurredin more difficult to detect silent sites such as the adrenalgland, liver, and deep lymph nodes. In addition, the percentageof patients demonstrating high NSE levels who were able to benefitfrom salvage chemotherapy was higher than for those who didnot (P<0.05). Our results indicate that serial NSE measurementsare useful for the early prediction of SCLC relapse and shouldhelp to facilitate early administration of salvage chemotherapyfor affected patients.(P<0.05)     

Characterization of a Novel Human Tumor Necrosis Factor-α Mutant with Increased Cytotoxic Activity

Various novel recombinant human tumor necrosis factor-α (TNF) mutants were prepared using protein engineering techniques, and their cytotoxic activity was compared with that of the intact form of TNF (intact TNF). Mutant 471 (a TNF mutant molecule with the deletion of 7 amino acids at the amino-terminal and the substitution of Pro⁸Ser⁹Asp¹⁰ by ArgLysArg) had a 6-fold higher cytotoxic activity against murine L929 cells. The mutant TNF had an increased ability to bind to TNF receptor on murine L929 fibroblasts cells. A cross-linking study revealed that mutant 471 had an increased ability to form an active trimer. Mutant 471 also showed higher cytotoxic activity against human KYM myosarcoma cells and human MIA PaCa-2 pancreatic carcinoma cells. The possible cachectin activity of the mutant was almost the same as that of intact TNF. These results suggest that mutant 471 might be a more promising candidate as an anticancer agent than intact TNF.     

Relationship between the Pharmacokinetics of Irinotecan and Diarrhea during Combination Chemotherapy with Cisplatin

Two phase I trials of irinotecan (CPT-11) in combination with cisplatin were conducted. In both cases, the dose-limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twenty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 at 80 or 90 mg/m² plus cisplatin at 60 mg/m². The other 13 patients received CPT-11 at 80 or 90 mg/m² plus cisplatin at 80 mg/m² with the granulocyte colony-stimulating factor support (2 μg/kg × 16 days). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT-11 was 90 mg/m² in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h after the start of CPT-11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3–4 diarrhea than those with a lower SN-38 level ( P =0.0003). Stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the development of diarrhea ( P =0.0021). We conclude that there is a clear relationship between the SN-38 concentration and diarrhea during chemotherapy with CPT-11 plus cisplatin.     

Rapid bactericidal activities of carbapenems against Pseudomonas aeruginosa in simulating human plasma concentrations

The rapid bactericidal activities of panipenem (PAPM), imipenem (IPM), and meropenem (MEPM) against Pseudomonas aeruginosa were investigated by using in vitro pharmacodynamic model simulating the human plasma concentrations after intravenous drip infusion at 500 mg for 0.5 hours. Against P. aeruginosa PAO1, PAPM and IPM showed rapider reduction in viable cell counts than MEPM at 0.5 hours after exposure. All drugs showed more than 3 log10 reduction in viable cell counts at 2 hours after exposure and bacterial regrowth was not observed throughout 6 hours. The initial bactericidal activities of the drugs against 4 clinical isolates within 1 hour after exposure were also investigated by the same method. Against P. aeruginosa strain 12,475, the 3 drugs showed similar initial bactericidal activity but PAPM and IPM showed stronger initial bactericidal activity than MEPM against the other strains as did against P. aeruginosa PAO1. The morphological change of a strain 12,489, for which the initial bactericidal activities were different largely, after 0.5 hours exposure to simulated drug-concentrations was investigated by scanning electron microscope. PAPM and IPM induced morphological changes in most of the cells and cell lysis and bulge formation. On the other hand, MEPM induced changes of the surface structure of cells and slightly elongated cells, but not cell lysis.