Multileafkollimator: Erweiterte Qualit?tssicherung an einem GE-Linearbeschleuniger

Hintergrund: Ein Multileafkollimator stellt durch die Vielzahl der Lamellen sehr viel höhere Ansprüche an die Konstanzprüfverfahren als ein konventionelles Blendensystem. Zur täglichen Kontrolle der Lamellenpositionierung wird ein Qualitssicherungskonzept vorgestellt. Methode: Zwei Feldkonfigurationen, die bei maximaler Öffnung der Blockblenden sowohl maximale Öffnung als auch "Overtravel" einzelner Lamellen enthalten, werden in täglichem Wechsel online vom Verifikationssystem zum Linearbeschleuniger übertragen. Im Lichtfeld des Linearbeschleunigers erfolgt eine visuelle Kontrolle der Lamellenpositionen mit Hilfe eines speziellen Prüfkörpers. Abschließend wird die Lamellenpositionierung mittels eines Electronic-Portal-Imaging-Systems dokumentiert und nach Überlagerung eines Gitters mit einer Referenzaufnahme verglichen. Ergebnisse: Die Methode stellt eine schnelle und effektive Möglichkeit dar, die Funktionsfähigkeit des gesamten Systems durch Simulation des "Routinebetriebs" zu überprüfen. Schlußfolgerung: Der Arbeits- und Zeitaufwand für die Qualitätssicherung an einem Multileafkollimator unterscheidet sich nur unwesentlich von dem eines konventionellen Blendensystems. Background: In comparison to a conventional collimator, a multileaf collimator demands a great deal of quality assurance procedures due to its large number of leaves. A concept for daily quality assurance is presented, mainly concerning the positioning accuracy of the leaves. Material and Methods: Two leaf configurations including maximal opening as well as overtravel of single leaves, at a maximal opening of the jaws, are transmitted online in daily exchange from our record- and verify system to the linac. Aiming at a special test phantom a visual control of the positioning accuracy is performed. The leaf positioning is documented by an electronic portal imaging system and is compared with a reference shot by superposition of a grid. Results: This method of quality assurance offers a fast and effective possibility to guarantee the proper function of the whole system by simulating the routine treatment situation. Conclusions: Compared to a conventional collimator only a slightly greater workload is needed for quality assurance of a multileaf collimator.     

Physicochemical Characterization of Protein-Free Low Density Lipoprotein Models and Influence of Drug Loading

Purpose. Drug free and drug loaded protein-free low density lipoprotein (LDL) models consisting mainly of phospholipids, cholesterol, cholesterol esters, and triglycerides in ratios found for physiological LDL have been prepared. Their physicochemical characteristics were compared with those of physiological LDL. Methods. Different characterization methods were used: photon correlation spectroscopy, transmission electron microscopy, X-ray solution scattering, and ¹H nuclear magnetic resonance spectroscopy (NMR). Results. Particle sizes are highly dependent on the preparation method and in particular on the homogenization conditions. Electron microscopy indicates that the size distributions of model systems are much broader than those of physiological LDL. The X-ray solution scattering patterns of the model systems display a temperature dependent maximum near 3.8 nm similar to that found in the patterns of physiological LDL. NMR indicates a comparable mobility of the lipid molecules in model particles and in physiological LDL. The influence of drug loading is similar to that found earlier for physiological LDL. In particular, the incorporation of the anti-cancer drug WB 4291 seems to have a fluidizing effect on the lipids in the core region of the particles. Conclusions. The preparation method of LDL model systems is of crucial importance as only the solvent evaporation method yielded systems in the size range of physiological LDL with acceptable high lipid concentrations. The fluidizing influence of temperature and drug incorporation (WB 4291) may be a disadvantage in drug targeting.     

Diffuse histiocytic lymphoma complicating chronic lymphocytic leukemia.

Nine patients with chronic lymphocytic leukemia (CLL) who also developed diffuse histiocytic lymphoma (DH) are described. The incidence of patients with CLL developing DH was at least 3.3%. CLL existed for a median of 2 years before the diagnosis of DH. DH presented in 8 patients with abdominal symptoms and/or enlarging lymph nodes, spleen and liver. There were no consistent laboratory abnormalities associated with the onset of DH. In 4 of the patients the DH appeared to be localized. Eight of the 9 patients have died with a median survival of 2 months from the diagnosis of DH. Whether DH occurs as a result of "blastic transformation" of pre-existing CLL or is a second, unrelated malignancy is not certain. It is hypothesized that utilizing current therapies for DH might favorably influence survival.     

Incidence of dementia in relation to stroke and the apolipoprotein E epsilon4 allele in the very old. Findings from a population-based longitudinal study

BACKGROUND AND PURPOSE: Both stroke and the apolipoprotein E (APOE) epsilon4 allele increase the risk of dementia. However, the interaction between stroke and APOE on dementia is still unclear. We addressed this topic by using a longitudinal design. METHODS: We followed up a community cohort of 1301 subjects aged >/=75 years, who did not have dementia at baseline. Among them, 92 subjects had a history of stroke (from 3 months to 16 years before baseline interview). After the 3-year follow-up, 224 dementia cases had been diagnosed. During the period of follow-up, 91 subjects had a first occurrence of stroke (incident stroke). The APOE genotype was known for 985 subjects. Cox proportional hazards regression models were constructed to estimate the risk for dementia in terms of relative risks (RRs) for stroke and the APOE epsilon4 allele, with adjustment for age, sex, education, systolic blood pressure, antihypertensive medication use, and heart disease. RESULTS: In the entire study population, RRs for dementia related to history of stroke and incident stroke were 1.7 (95% CI, 1.1 to 2.6) and 2.4 (95% CI, 1.6 to 3.5), respectively, after adjustment for all potential confounders. Subjects with stroke that occurred within 3 years before baseline had RR of 2.4 (95% CI, 1.4 to 4.2), whereas those with stroke occurring >3 years before baseline had RR of dementia of 1.1 (95% CI, 0.6 to 2.3). Among those with APOE information, individuals with only history of stroke (that occurred within 3 years before baseline) had RR of 3.1 (95% CI, 1.4 to 6.6), individuals with only the APOE epsilon4 allele had RR of 1.7 (95% CI, 1.1 to 2.5), and individuals with both factors had RR of 5.3 (95% CI, 2.1 to 13.4). The corresponding figures when incident stroke was examined instead of history of stroke were 2.3 (95% CI, 1.3 to 4.1), 1.7 (95% CI, 1.1 to 2.4), and 4.6 (95% CI, 2.0 to 10.6), respectively. The RR of interaction term for history of stroke and APOE epsilon4 was 1.1 (95% CI, 0.3 to 3.8; P=0.8). The corresponding figure was 1.2 (95% CI, 0.4 to 4.4; P=0.7) for incident stroke and APOE epsilon4. Furthermore, the RRs of dementia without any stroke and dementia with stroke in relation to APOE epsilon4 were 1.6 (95% CI, 1.1 to 2.3) and 1.2 (95% CI, 0.6 to 2.4), respectively. In addition, the APOE epsilon4 allele was not significantly related to the occurrence of stroke (RR=0.8; 95% CI, 0.5 to 1.5). CONCLUSIONS: A relatively fresh stroke is a risk factor for dementia. APOE epsilon4 increases the risk of dementia without stroke but not dementia with stroke. Our data do not support a multiplicative effect of stroke and the APOE epsilon4 allele on the risk of dementia. However, both factors seem to have an additive effect on the risk of dementia. The APOE epsilon4 allele does not increase the risk of stroke in this Swedish elderly population.     

Abrin Poisoning

Abrin is a toxic protein obtained from the seeds of Abrus precatorius (jequirity bean), which is similar in structure and properties to ricin. Abrin is highly toxic, with an estimated human fatal dose of 0.1–1 µg/kg, and has caused death after accidental and intentional poisoning. Abrin can be extracted from jequirity beans using a relatively simple and cheap procedure. This satisfies one criterion of a potential chemical warfare agent, although the lack of large scale production of jequirity seeds means that quantity is unavailable for ready mass production of abrin for weapons. This contrasts with the huge cultivation of Ricinus seeds for castor oil production. At the cellular level, abrin inhibits protein synthesis, thereby causing cell death. Many of the features observed in abrin poisoning can be explained by abrin-induced endothelial cell damage, which causes an increase in capillary permeability with consequent fluid and protein leakage and tissue oedema (the so-called vascular leak syndrome). Most reported cases of human poisoning involve the ingestion of jequirity beans, which predominantly cause gastrointestinal toxicity. Management is symptomatic and supportive. Experimental studies have shown that vaccination with abrin toxoid may offer some protection against a subsequent abrin challenge, although such an approach is unlikely to be of benefit in a civilian population that in all probability would be unprotected.     

Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II).

PURPOSE: A Phase I/IIb multicenter study was conducted to evaluate the safety and immunogenicity of the anti-idiotypic antibody vaccine ACA125 that functionally imitates the tumor antigen CA125 in 119 patients with advanced ovarian carcinoma. A preliminary report on the initial 42 patients demonstrated safety and immunogenicity. EXPERIMENTAL DESIGN: Using the complete intention-to-treat population (n = 119) who received a mean of 9.7 ACA125 applications, survival was analyzed with respect to immunological responses. RESULTS: In 81 patients (68.1%), a specific anti-anti-idiotypic antibody (Ab3) response could be induced. Additionally, the development of CA125-specific antibodies (Ab1') and antibody-dependent cell-mediated cytotoxicity of CA125-positive tumor cells was observed in 50.4% and 26.9% of patients, respectively. The median survival of all patients was 19.4 months (range, 0.5-56.1 months). Ab3-positive patients showed a significantly longer survival (median, 23.4 months; P < 0.0001) as compared with Ab3-negative patients (median, 4.9 months). A positive Ab3 response remained associated with longer survival when controlling for other prognostic factors including FIGO (International Federation of Gynecologists and Obstetricians) stage, response to and type of first-line chemotherapy, number of previous treatments, or concomitant antitumor therapy. With regard to safety, repeated vaccination was well tolerated. No serious adverse events related to the application of ACA125 occurred. CONCLUSIONS: Although the uncontrolled design of this study prevents definitive conclusions with respect to subgroups, the data support a relationship between Ab3 response and survival time. Thus, the need for further randomized, controlled clinical trials to establish efficacy of the vaccine ACA125 seems to be indicated.     

Antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin: an orally bioavailable heat shock protein 90 modulator.

PURPOSE: The purpose of this study was to investigate the antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; NSC707545), a water-soluble benzoquinone ansamycin. EXPERIMENTAL DESIGN: The activity of 17-DMAG, in vivo, was evaluated for inhibition of fibroblast growth factor (FGF)-2-induced angiogenesis in s.c. implanted Matrigel in mice. In vitro, the activity of 17-DMAG on endothelial cells (human umbilical vein endothelial cells; HUVEC) was tested in FGF-2; and vascular endothelial growth factor (VEGF)-induced proliferation and apoptosis, motility, and extracellular matrix invasion; and on the alignment of capillary like structures in Matrigel. The protein level of heat shock protein (Hsp)90 and client proteins was examined by Western blot in FGF-2 and VEGF-stimulated HUVEC. RESULTS: Daily oral administration of 17-DMAG affected the angiogenic response in Matrigel in a dose-dependent manner. The hemoglobin content in the Matrigel implants was significantly inhibited, and the histological analysis confirmed a decrease of CD31(+) endothelial cells and of structures organized in cord and erythrocyte-containing vessels. In vitro, the compound inhibited dose-dependently the migration and the extracellular matrix-invasiveness of HUVEC and their capacity to form capillary like structures in Matrigel. 17-DMAG treatment also inhibited FGF-2 and VEGF-induced HUVEC proliferation and resulted in apoptosis. Accordingly, the expression of Hsp90 direct client proteins (pAkt and c-Raf-1) or their downstream substrates including pERK was also affected. 17-DMAG consistently increased the expression of Hsp70. Throughout the study similar results were obtained with 17-allylamino-17-demethoxygeldanamycin (17-AAG; NSC330507), the analog compound currently undergoing clinical trials. CONCLUSIONS: We show that the Hsp90 targeting agents 17-DMAG and 17-AAG inhibit angiogenesis. The strong effects on endothelial cell functions, in vitro, indicate that the antiangiogenic activity of 17-DMAG/17-AAG could also be due to a direct effect on endothelial cells. The oral bioavailability of 17-DMAG might be of advantage in investigating the potential of this compound in clinical trials with antiangiogenic as well as antiproliferative endpoints.     

Reducing weight gain in children through enhancing physical activity and nutrition: the APPLE project.

OBJECTIVE: Community-based lifestyle intervention may offer the best means of reducing the global epidemic of childhood obesity and its consequences, yet few successful interventions have been reported. The objective was to determine whether increasing extra-curricular levels of activity could reduce weight gain in children. METHODS: A controlled intervention study was conducted using standardised methods to assess outcomes. Two comparable relatively rural communities in Otago, New Zealand formed intervention and control settings. Height, weight, waist circumference and participation in physical activity (by accelerometry) were measured at baseline and at 1 year in 384 children aged 5 to 12 years representing the majority of children in this age group in intervention and control communities. Community Activity Co-ordinators were employed at each school in the intervention area. Their brief was to widen exposure to activity and engage children not interested in traditional sporting activities by encouraging lifestyle-based activities (e.g. walking) and non-traditional sports (e.g. golf and taekwondo) during extra-curricular time at school, after school and during vacations. Simple dietary advice was offered and the wider community was encouraged to participate. RESULTS: Average accelerometry counts at 1 year were 28% (95% CI: 11 to 47%) higher in intervention compared with control children after adjusting for age, sex, baseline values and school. Intervention children spent less time in sedentary activity (ratio 0.91, p = 0.007) and more time in moderate (1.07, p = 0.001) and moderate/vigorous (1.10, p = 0.01) activity. Adjusted mean BMI Z-score was lower in intervention relative to control children by -0.12 units (95% CI: -0.22 to -0.02). CONCLUSION:. An intervention designed to maximise opportunities for physical activity during extra-curricular time at school and during leisure time through the provision of community-based Activity Co-ordinators significantly increased participation in physical activity and slowed unhealthy weight gain in primary school-aged children.     

Social-cognitive and school factors in lifetime smoking among adolescents

BACKGROUND: Smoking is a serious health threat and identifying risk factors for smoking is thus of great importance. The aim of the study was to examine the effects of social-cognitive factors and school factors on lifetime smoking status among adolescents. METHODS: The study was based on cross-sectional data on 2,913 Danish adolescents in grade 7 attending 118 randomly selected public schools. Social-cognitive factors were examined with five measures: self-efficacy to resist pressure to smoke, social influence (norms), social influence (behavior), social influence (pressure), and attitude. We used multilevel analyses to estimate the associations between social-cognitive factors and lifetime smoking status as well as the group-level effects of school, school class, and gender group in the school class. RESULTS: Each social-cognitive factor was significantly associated with lifetime smoking status, even when several potential confounders and the effects of school, school class, and gender group were taken into account. Of the three group-level school factors, gender group in the school class had the strongest effect on smoking status. CONCLUSION: We conclude that self-efficacy to resist pressure to smoke, attitude, and the three types of social influence are significantly associated with lifetime smoking status, even when the effects of group-level school factors are taken into account. The strong effect of gender group in school class on lifetime smoking status indicates that prevention actions should address the social context of adolescents.