Impact of genetic targets on primary brain tumor therapy: what's ready for prime time?

Primary brain tumors constitute a substantial public health problem with 66,290 cases diagnosed in the US in 2012, and 13,700 deaths recorded. With discovery of genetic factors associated with specific brain tumor subtypes, the goal of therapy is changing from treating a class of tumors to developing individualized therapies catering to the molecular composition of the actual tumor. For oligodendrogliomas, the loss of 1p/19q due to an unbalanced translocation improves both survival and the response to therapy, and is thus both a prognostic and a predictive marker. Several additional genetic alterations such as EGFR amplification, MGMT methylation, PDGFR activation, and 9p and 10q loss, have improved our understanding of the characteristics of these tumors and may help guide therapy in the future. For astrocytic tumors, MGMT is associated with a better prognosis and an improved response to temozolomide, and for all glial tumors, mutations in the IDH1 gene are possibly the most potent of good prognostic markers. Three of these markers - 1p/19q deletions, MGMT methylation status, and mutations in the IDH1 gene - are so potent that a new brain tumor subtype, the "triple negative" glioma (1p/19q intact, MGMT unmethylated, IDH1 non-mutated) has entered common parlance. Newer markers, such as CD 133, require additional investigation to determine their prognostic and predictive utility. In medulloblastomas, markers of WNT activation, MYCC/MCYN amplification, and TrkC expression levels are reliable prognostic indicators, but do not yet drive specific treatment selection. Many other proposed markers, such as 17q gain, TP53 mutations, and hMOF protein expression show promise, but are not yet ready for prime time. In this chapter, we focus on the markers that have shown convincing prognostic, predictive, and diagnostic value, and discuss potential markers that are being currently being intensively investigated. We also discuss serum profiling of tumors in an effort to discover additional potential markers.

Antibacterial resistance of community-acquired respiratory tract pathogens recovered from patients in Latin America: results from the PROTEKT surveillance study (1999-2000).

PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a global surveillance study established in 1999 to monitor antibacterial resistance of respiratory tract organisms. Thirteen centers from Argentina, Brazil and Mexico participated during 1999-2000; they collected 1806 isolates (Streptococcus pneumoniae 518, Haemophilus influenzae 520, Moraxella catarrhalis 140, Staphylococcus aureus 351, S. pyogenes 277). Overall, 218 (42.1%) of the S. pneumoniae isolates had reduced susceptibility to penicillin, 79 (15.3%) were penicillin-resistant and 79 (15.3%) were erythromycin-resistant. Mexico had the highest prevalence of penicillin (76.5%) and erythromycin (31.2%) resistance. Of 77 erythromycin-resistant S. pneumoniae tested for resistance genotype, 43 possessed mef(A), 33 possessed erm(B) and 1 possessed both erm(B) and mef(A) mechanism. All S. pneumoniae isolates were fully susceptible to telithromycin, linezolid, teicoplanin and vancomycin. Among H. influenzae isolates, 88 (16.9%) produced beta-lactamase, ranging from 11% (Brazil) to 24.5% (Mexico). Among M. catarrhalis isolates, 138 (98.6%) produced beta-lactamase. Twenty-four (8.7%) of the S. pyogenes isolates were erythromycin-resistant; resistance being attributable to mefA (n=18), ermTR (n=5) and ermB (n=1). All H. influenzae, M. catarrhalis and S. pyogenes were fully susceptible to telithromycin. Methicillin resistance was found in 26.5% of the S. aureus isolates (Argentina 15%; Mexico 20%; Brazil 31.3%). Telithromycin was effective against 97.7% of methicillin-susceptible isolates. PROTEKT confirms that antibacterial resistance is an emerging problem in Latin America. The previously reported high levels of pneumococcal resistance to the beta-lactam and macrolides were exceeded. New agents that do not induce resistance or that exert low selective pressure, e.g. telithromycin, are essential to safeguard future antibacterial efficacy.

Antibacterial resistance of community-acquired respiratory tract pathogens recovered from patients in Latin America: results from the PROTEKT surveillance study (1999-2000)

PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a global surveillance study established in 1999 to monitor antibacterial resistance of respiratory tract organisms. Thirteen centers from Argentina, Brazil and Mexico participat ed during 1999-2000; they collected 1,806 isolates (Streptococcus pneumoniae 518, Haemophilus influenzae 520, Moraxella catarrhalis 140, Staphylococcus aureus 351, S. pyogenes 277). Overall, 218 (42.1 percent) of the S. pneumoniae isolates had reduced susceptibility to penicillin, 79 (15.3 percent) were penicillin-resistant and 79 (15.3 percent) were erythromycin-resistant. Mexico had the highest prevalence of penicillin (76.5 percent) and erythromycin (31.2 percent) resistance. Of 77 erythromycin-resistant S. pneumoniae tested for resistance genotype, 43 possessed mef(A), 33 possessed erm(B) and 1 possessed both erm(B) and mef(A) mechanism. All S. pneumoniae isolates were fully susceptible to telithromycin, linezolid, teicoplanin and vancomycin. Among H. influenzae isolates, 88 (16.9 percent) produced b-lactamase, ranging from 11 percent (Brazil) to 24.5 percent (Mexico). Among M. catarrhalis isolates, 138 (98.6 percent) produced b-lactamase. Twenty-four (8.7 percent) of the S. pyogenes isolates were erythromycin-resistant; resistance being attributable to mefA (n=18), ermTR (n=5) and ermB (n=1). All H. influenzae, M. catarrhalis and S. pyogenes were fully susceptible to telithromycin. Methicillin resistance was found in 26.5 percent of the S. aureus isolates (Argentina 15 percent; Mexico 20 percent; Brazil 31.3 percent). Telithromycin was effective against 97.7 percent of methicillin-susceptible isolates. PROTEKT confirms that antibacterial resistance is an emerging problem in Latin America. The previously reported high levels of pneumococcal resistance to the b-lactam and macrolides were exceeded. New agents that do not induce resistance or that exert low selective pressure, e.g. telithromycin, are essential to safeguard future antibacterial efficacy

Infecçöes relacionadas ao cateter venoso central em terapia intensiva / Central venous catheter-related infections in critically-ill-patients

OBJETIVO. Determinar a incidência, a etiologia e os fatores de risco das infecçoes relacionadas ao cateter venoso central em terapia intensiva. METODOLOGIA. Estudo observacional de coorte, prospectivo, em pacientes criticamente enfermos submetidos à cateterizaçao venosa profunda por punçao percutânea. Realizadas culturas quantitativa da pele, semiquantitativa da ponta e quantitativa do canhao do cateter, e hemocultura periférica. Os possíveis fatores de risco foram submetidos à análise univariada e multivariada. RESULTADOS. Foram estudados 57 períodos de cateterizaçao em 51 pacientes. A incidência de infecçao local foi de 21,1 por cento (33,8/1.000 dias-cateter), e de bacteremia, 8,7 por cento (l4,1/1.000 dias-cateter). A pele no local de inserçao estava colonizada em 32,7 por cento dos pacientes e o canhao, em 29,1 por cento. A origem dos microrganismos causadores de infecçao foi a pele em 41,2 por cento, o canhao em 29,4 por cento, infecçao a distância em 5,9 por cento, e nao ficou esclarecida em 23,5 por cento dos casos. Estafilococos coagulase-negativa foram os agentes etiológicos predominantes. Identificou-se, como variáveis independentemente associadas à infecçao local, a purulência no orifício de inserçao e a utilizaçao de outro dispositivo intravascular. As variáveis independentemente associadas à bacteremia foram a inserçao na veia jugular interna e a colonizaçao do canhao do cateter. CONCLUSOES. A bacteremia é uma complicaçao importante do cateterismo venoso central em terapia intensiva. Os estafilococos coagulase-negativa predominam nesta modalidade de infecçao hospitalar. A inserçao do cateter na veia jugular interna e a colonizaçao do canhao aumentam o risco de bacteremia relacionada à linha venosa central.

[Central venous catheter-related infections in critically ill patients]. / Infecções relacionadas ao cateter venoso central em terapia intensiva.

BACKGROUND: To determine incidence rate, etiology and risk factors for central venous catheter (CVC)-related infections in critically-ill patients, a prospective cohort study was conducted in the general Intensive Care Unit (ICU) of a 212 bed Hospital in Florianópolis, Brazil. MATERIAL AND METHOD: Patients admitted to ICU between May 1993 and February 1994, exposed to short-term CVC, were included in the study. Quantitative skin culture at CVC insertion site, semi-quantitative CVC tip culture, quantitative hub culture, and peripheral blood-culture were done. Results were submitted to univariate and multivariate analysis. RESULTS: Fifty-seven catheterization periods were analysed in 51 patients. The incidence rate was 21.1% (33.1 per 1,000 catheter-days) for local infection, and 8.7% (14.1 per 1,000 catheter-days) for catheter-associated bacteremia. The skin at the insertion site was colonized in 32.7% and the hub in 29.1% of the patients respectively. Potential sources of infection were the skin in 41.2% of the cases, the hub in 29.4%, remote site in 5.9% and unknown in 23.5%. The hub was implicated in 60% of the catheter-associated bacteremias. Coagulase-negative staphylococci were the main isolates. Another intravascular device and purulence at the insertion site were independently associated with local infection. Insertion at internal jugular site and hub colonization were independently associated with bacteremia. CONCLUSIONS: Catheter-associated bacteremia is a major complication of central venous catheterization in critically-ill patients. Internal jugular insertion and CVC hub colonization are important risk factors for significant catheter-related infections.