Do medulloblastoma tumors meet the food and drug administration criteria for anti‐erbB2 therapy with trastuzumab?

Several publications have recently focused on the erbB2 receptor in pediatric medulloblastomas (MBs) and its prognostic consequence. We determined erbB2 expression in 23 MBs at diagnosis. After DNA extraction, quantitative PCR targeting the erbB2 gene was performed and correlated with FISH analysis and immunohistochemistry. The samples were representative of the spectrum of the disease apart from the absence of large cell MBs. Using the tools validated for breast cancers by the FDA, we did not observe any expression or amplification of erbB2 and hence we speculate that MBs are not a good target for treatment with anti-erbB2 antibodies.     

Vaccination coverage and sociodemographic determinants of measles–mumps–rubella vaccination in three different age groups

WHO-Europe's goal is to eliminate measles and rubella by 2010 which will require a coverage rate of 95% for both MMR-vaccine doses. Belgian recommendations include a first MMR vaccine at 12 months and a second at 10-12 years of age. To survey MMR vaccination coverage, EPI two-stage random cluster samples of 1,500 toddlers (18-24 months of age), 900 primary school children (born in 1997), and 1,500 adolescents (born in 1991) living in Flanders (Belgium) were drawn. Documented MMR-vaccination was recorded and a questionnaire on sociodemographic factors was completed at home by trained interviewers in 2005. Missing data were retrieved from well-baby clinics and school health service documents. The overall response rate was 89.5%, leaving 3,490 subjects fit for analysis. MMR coverage (first dose) was 94.0% in the toddler group, 88.0% in the 7-year-olds, and 80.6% in adolescents. The 10- to 12-year dose was documented in 83.6% of the adolescents, but only 74.6% had proof of both MMR vaccines. A lower MMR coverage was noted in single or divorced parents (toddlers, adolescents), families with more than four children (toddlers, adolescents), non-Belgian parental origin (children, adolescents), lower education or unemployment of parents (toddlers, children, adolescents), low family income (children, adolescents), vaccination by the GP (toddlers, children), and education-related factors (children, adolescents). The recommended WHO coverage rate of 95% for MMR is within reach in toddlers. Documentation of vaccination is a major concern in older age groups and may explain lower coverage estimates. Children growing up in a less privileged environment deserve special attention.     

Air Pollution–Related Prothrombotic Changes in Persons with Diabetes

Background

Population studies suggest that persons with diabetes are more sensitive to the effects of particulate matter (PM) air pollution. However, the biological mechanisms of a possible prothrombotic effect underlying this enhanced susceptibility remain largely unknown.

Objective

We hypothesized that exposure to PM causes prothrombotic changes in persons with diabetes, possibly via systemic inflammation.

Methods

Our study included 137 nonsmoking adults with diabetes who were outpatients at the University Hospital Leuven. Recent exposure (2 hr before examination) to ambient PM was measured at the entrance of the hospital. Individual chronic exposure to PM was assessed by measuring the area occupied by carbon in airway macrophages obtained by sputum induction. Platelet function was measured ex vivo with the PFA-100 platelet function analyzer, which simulates a damaged blood vessel; we analyzed the function of platelets in primary hemostasis under high shear conditions. Total and differential blood leukocytes were counted.

Results

Independent of antiplatelet medication, an interquartile range (IQR) increase of 39.2 μg/m³ in PM₁₀ (PM with aerodynamic diameter ≤ 10 μm) concentration measured 2 hr before the clinical examination (recent exposure) was associated with a decrease of 21.1 sec [95% confidence interval (CI), − 35.3 to − 6.8] in the PFA-100 closure time (i.e., increased platelet activation) and an increase in blood leukocytes of 512 per microliter of blood (95% CI, 45.2–979). Each area increase of 0.25 μm² (IQR) in carbon load of airway macrophages (chronic exposure) was associated with an increase of 687 leukocytes per microliter of blood (95% CI, 224–1,150).

Conclusions

A relevant increase in recent PM exposure was associated with a change in platelet function toward a greater prothrombotic tendency. The magnitude of the change was about two-thirds (in the opposite direction) of the average effect of antiplatelet medication. Diabetic patients showed evidence of proinflammatory response to both recent and chronic exposure to PM air pollution.     

Tissue factor mediates the HGF/Met-induced anti-apoptotic pathway in DAOY medulloblastoma cells

The classical treatment scheme for medulloblastoma (MB) is based on a tri-therapy approach consisting of surgical tumor resection, craniospinal axis radiation and chemotherapy. With current treatments relying mainly on non-specific cytotoxic therapy, a better understanding of the mechanisms underlying resistance to these treatments is important in order to improve their effectiveness. In this study, we report that stimulation of DAOY with HGF resulted in the protection of these cells against etoposide-induced apoptosis, this anti-apoptotic effect being correlated with an increase in the expression of tissue factor (TF), the initiator of the extrinsic pathway of coagulation. HGF-mediated protection from apoptosis was abolished by a c-Met inhibitor as well as by siRNA-mediated reduction of TF levels, implying a central role of Met-dependent induction of TF expression in this process. Accordingly, stimulation of DAOY with FVIIa, the physiological ligand of TF, also resulted in a significant protection from etoposide-mediated cytotoxicity. Overall, our results suggest the participation of the haemostatic system to drug resistance in MB and may thus provide novel therapeutic approaches for the treatment of these tumors.     

Secular trends in breast cancer mortality in five East Asian populations: Hong Kong,Japan, Korea,Singapore and Taiwan

Breast cancer risk is increasing in most Asian female populations, but little is known about the long‐term mortality trend of the disease among these populations. We extracted data for Hong Kong (1979–2005), Japan (1963–2006), Korea (1985–2006), and Singapore (1963–2006) from the World Health Organization (WHO) mortality database and for Taiwan (1964–2007) from the Taiwan cancer registry. The annual age‐standardized, truncated (to ≥20 years) breast cancer death rates for 11 age groups were estimated and joinpoint regression was applied to detect significant changes in breast cancer mortality. We also compared age‐specific mortality rates for three calendar periods (1975–1984, 1985–1994, and 1995–2006). After 1990, breast cancer mortality tended to decrease slightly in Hong Kong and Singapore except for women aged 70+. In Taiwan and Japan, in contrast, breast cancer death rates increased throughout the entire study period. Before the 1990s, breast cancer death rates were almost the same in Taiwan and Japan; thereafter, up to 1996, they rose more steeply in Taiwan and then they began rising more rapidly in Japan than in Taiwan after 1996. The most rapid increases in breast cancer mortality, and for all age groups, were in Korea. Breast cancer mortality trends are expected to maintain the secular trend for the next decade mainly as the prevalence of risk factors changes and population ages in Japan, Korea, and Taiwan. Early detection and treatment improvement will continue to reduce the mortality rates in Hong Kong and Singapore as observed in Western countries. (Cancer Sci 2010; 101: 1141–1246)     

Improved OMV vaccine against Neisseria meningitidis using genetically engineered strains and a detergent-free purification process

The use of detergent-extracted outer membrane vesicles (OMVs) is an established approach for development of a multivalent PorA vaccine against N. meningitidis serogroup B. Selective removal of lipopolysaccharide (LPS) decreases toxicity, but promotes aggregation and narrows the immune response. Detergent-free OMV vaccines retain all LPS, which preserves the native vesicle structure, but result in high toxicity and lower yield. The present study assessed the effects of gene mutations that attenuated LPS toxicity (lpxL1) or improved OMV yield (rmpM) in combination with the available OMV purification processes. The results substantiate that OMVs from a strain with both mutations, produced with a detergent-free process provide better vaccine characteristics than the traditional detergent-based approach. With comparable toxicity and yield, no aggregation and cross-protection against other PorA subtypes, these OMV vaccines are potentially safe and effective for parenteral use in humans.     

An assessment of the interindividual variability of internal dosimetry during multi-route exposure to drinking water contaminants

The objective of this study was to evaluate inter-individual variability in absorbed and internal doses after multi-route exposure to drinking water contaminants (DWC) in addition to the corresponding variability in equivalent volumes of ingested water, expressed as liter-equivalents (LEQ). A multi-route PBPK model described previously was used for computing the internal dose metrics in adults, neonates, children, the elderly and pregnant women following a multi-route exposure scenario to chloroform and to tri- and tetra-chloroethylene (TCE and PERC). This scenario included water ingestion as well as inhalation and dermal contact during a 30-min bathroom exposure. Monte Carlo simulations were performed and distributions of internal dose metrics were obtained. The ratio of each of the dose metrics for inhalation, dermal and multi-route exposures to the corresponding dose metrics for the ingestion of drinking water alone allowed computation of LEQ values. Mean BW-adjusted LEQ values based on absorbed doses were greater in neonates regardless of the contaminant considered (0.129-0.134 L/kg BW), but higher absolute LEQ values were obtained in average adults (3.6-4.1 L), elderly (3.7-4.2 L) and PW (4.1-5.6 L). LEQ values based on the parent compound's AUC were much greater than based on the absorbed dose, while the opposite was true based on metabolite-based dose metrics for chloroform and TCE, but not PERC. The consideration of the 95th percentile values of BW-adjusted LEQ did not significantly change the results suggesting a generally low intra-subpopulation variability during multi-route exposure. Overall, this study pointed out the dependency of the LEQ on the dose metrics, with consideration of both the subpopulation and DWC.     

Glycated hemoglobin in pregnancies at increased risk for gestational diabetes mellitus

Objective

The glycated hemoglobin (HbA_1c) value is increasingly used for the detection of (pre)diabetes, but HbA_1c decreases during pregnancy. We sought to identify clinical and metabolic correlates of HbA_1c in pregnancies at increased risk for gestational diabetes mellitus (GDM).

Study design

We prospectively studied 335 gravidas who received a 3-h 100 g oral glucose tolerance test (OGTT) at 24–32 weeks, in most cases after an abnormal glucose challenge test. Several indices of insulin sensitivity and secretion were computed from fasting measurements and the OGTT.

Results

HbA_1c concentrations gradually increased in diet-treated and insulin-treated GDM gravidas compared with non-GDM gravidas. HbA_1c was higher if the insulin peak was delayed until 180 min compared with 60 or 120 min. Stepwise regression identified the homeostasis modeling assessment of insulin resistance (HOMA-IR) as the first-rank correlate. Other correlates were ethnicity, a low insulin-to-glucose response at 60 min, and gestational age. The HbA_1c value corresponding to a fasting glucose of 5.1 mmol/l (diagnostic of GDM) was 2 mmol/mol (∼0.2%) higher if sampling occurred at 29–32 vs. 24–28 weeks or if ancestry was non-European vs. European.

Conclusion

HbA_1c is strongly associated with insulin resistance; in addition, HbA_1c captures the first-phase insulin response. However, HbA_1c varies with gestational age and ethnicity.