Buchbesprechungen

Ohne Zusammenfassung     

Beitrag zum Mechanismus der Bilirubinreaktion im Blut

Ohne Zusammenfassung     

Ein Beitrag zur Frage: Polyneuritis mercurialis oder syphilitica?

Ohne ZusammenfassungVortrag, gehalten in der Dermatologen-Vereinigung des rheinischwestphälischen Industriebezirks in Düsseldorf am 28. April 1901.     

Validation of Adult Relative Radiation Levels Using the ACR Dose Index Registry: Report of the ACR Appropriateness Criteria Radiation Exposure Subcommittee

The ACR Dose Index Registry (DIR) provides a new source of clinical radiation exposure data that has not been used previously to establish or update the relative radiation level (RRL) values in the ACR Appropriateness Criteria (AC). The results of a recent review of DIR data for 10 common CT examinations were compared with current ACR AC RRL values for the same procedures. The AC RRL values were previously determined by consensus of members of the AC Radiation Exposure Subcommittee based on reference radiation dose values from the literature (when available) and anecdotal information from individual members’ clinical practices and experiences. For 7 of the 10 examination types reviewed, DIR data agreed with existing RRL values. For 3 of 10 examination types, DIR data reflected lower dose values than currently rated in the AC. The Radiation Exposure Subcommittee will revise these RRL assignments in a forthcoming update to the AC (in October 2018) and will continue to monitor the DIR and associated reviews and analyses to refine RRL assignments for additional examination types. Given recent attention and efforts to reduce radiation exposure in CT and other imaging modalities, it is likely that other examination types will require revision of RRL assignments once information from the DIR database is considered.     

EORTC 26083 phase I/II trial of dasatinib in combination with CCNU in patients with recurrent glioblastoma

The treatment of patients with recurrent glioblastoma remains a major oncologic problem, with median survival after progression of 7–9 months. To determine the maximum tolerated dose and dose-limiting toxicity (DLT), the combination of dasatinib and cyclonexyl-chloroethyl-nitrosourea (CCNU) was investigated in this setting. The study was designed as multicenter, randomized phase II trial, preceded by a lead-in safety phase. The safety component reported here, which also investigated pharmacokinetics and preliminary clinical activity, required expansion and is therefore considered a phase I part to establish a recommended dosing regimen of the combination of CCNU (90–110 mg/m²) and dasatinib (100–200 mg daily). Overall, 28 patients were screened, and 26 patients were enrolled. Five dose levels were explored. DLTs, mainly myelosuppression, occurred in 10 patients. Grade 3 or 4 neutropenia was recorded in 7 patients (26.9%) and thrombocytopenia in 11 patients (42.3%). No significant effect of CCNU coadministration on dasatinib pharmacokinetics was found. Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2–1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents.     

Factors influencing the acceleration of human factor XIa inactivation by antithrombin III

Controversy exists in the literature concerning the potentiating effect of heparin on the inactivation rate of factor XIa by antithrombin III (AT III) in both purified systems and in plasma. We have analyzed the factors that could influence this reaction and found that ionic strength of the medium, as well as the type and concentration of the heparin preparations accounted for the major discrepancies in the literature. At I = 0.43 N, a preparation of bovine lung heparin at 1 U/mL did not augment the inactivation rate of factor XIa by inhibitors in plasma or by purified AT III. However, when ionic strength was decreased, a progressive increase in the potentiating effect was observed, reaching 6.5-fold at I = 0.15 N. At saturating concentrations of heparin, which results in the formation of 100% AT III-heparin complex, (greater than ten-fold molar excess over AT III) in purified systems, all heparin preparations (porcine, bovine, low molecular weight [LMW], and high affinity) yielded an approximately 30-fold augmentation of the factor XIa inactivation rate. However, when heparin was less than saturating, we observed that various heparin preparations affected the AT III-induced inactivation of factor XIa to different degrees even though they exhibited the same inhibitory activity (1 U/mL) against thrombin. This variation resulted from differences in the number of AT III binding sites in each heparin preparation, despite a similar Kd for each. Addition of high molecular weight kininogen (HK) to AT III-heparin complexes did not enhance their ability to inhibit factor XIa, and high concentrations of HK decreased the inactivation rate. A high therapeutic dose of heparin only permits the formation of 2.5% to 16.5% of the AT III-heparin complexes that can be achieved at saturation. We observed that 1 U/mL heparin (bovine lung heparin) (high therapeutic concentration) in virtually undiluted plasma only accelerated the inactivation rate of factor XIa (in the absence of other active enzymes) less than two-fold. These new observations further support our previous conclusion that therapeutic levels of heparin have little to no influence on the inactivation rate of factor XIa in plasma.