CNS germinomas represent a unique germ cell tumor entity characterized by undifferentiated tumor cells and a high response rate to current treatment protocols. Limited information is available on their underlying genomic, epigenetic and biological alterations. We performed a genome-wide analysis of genomic copy number alterations in 49 CNS germinomas by molecular inversion profiling. In addition, CpG dinucleotide methylation was studied by immunohistochemistry for methylated cytosine residues. Mutational analysis was performed by resequencing of candidate genes including KIT and RAS family members. Ras/Erk and Akt pathway activation was analyzed by immunostaining with antibodies against phospho-Erk, phosho-Akt, phospho-mTOR and phospho-S6. All germinomas coexpressed Oct4 and Kit but showed an extensive global DNA demethylation compared to other tumors and normal tissues. Molecular inversion profiling showed predominant genomic instability in all tumors with a high frequency of regional gains and losses including high level gene amplifications. Activating mutations of KIT exons 11, 13, and 17 as well as a case with genomic KIT amplification and activating mutations or amplifications of RAS gene family members including KRAS, NRAS and RRAS2 indicated mutational activation of crucial signaling pathways. Co-activation of Ras/Erk and Akt pathways was present in 83% of germinomas. These data suggest that CNS germinoma cells display a demethylated nuclear DNA similar to primordial germ cells in early development. This finding has a striking coincidence with extensive genomic instability. In addition, mutational activation of Kit-, Ras/Raf/Erk- and Akt- pathways indicate the biological importance of these pathways and their components as potential targets for therapy.
Febrile neutropenia is still associated with a high mortality rate, making timely and efficient empirical antibiotic therapy absolutely vital. For these reasons, evidence-based guidelines are urgently needed. The guidelines published so far are mainly based on clinical experience and selective citation. This review summarises studies and meta-analyses concerning empirical antibiotic therapy in high-risk neutropenic patients: (1) No benefit results from the addition of an aminoglycoside to the initial empirical therapy. On the contrary, patients who received an aminoglycoside had a significantly higher rate of adverse events, especially nephrotoxicity. (2) The empirical addition of a glycopeptide after 3-4 days of persistent fever was evaluated in two randomised controlled trials. Combined analysis demonstrates that in clinically stable patients without resistant or skin/soft tissue infections, the use of a glycopeptide can be delayed for another 3-4 days. (3) The choice of drugs for monotherapy is currently being evaluated; preliminary results demonstrate that ceftazidime has a significantly inferior response rate (without modification) to other evaluated antibiotics. In conclusion, guidelines should be based on the systematic evaluation of all relevant clinical trials. The analysis of the existing data leads to the recommendation of monotherapy, without aminoglycoside, using piperacillin-tazobactam, cefepime, meropenem or imipenem-cilastin, any of which may be continued for up to 7 days in persistently febrile, clinically stable patients without skin/soft tissue infections. The choice of drug as standard first-line therapy should depend on drug costs, local resistance rates and the potential for resistance induction.
A simple, accurate, sensitive, and precise reversed-phase (RP) high-performance liquid chromatographic (HPLC) method with fluorescence detection allowing the sensitive and specific quantitation of the newer fluoroquinolones levofloxacin and moxifloxacin is described. Moxifloxacin is used as the internal standard for the determination of levofloxacin and vice versa. A single-step liquid-liquid extraction from human plasma is sufficient for both quinolones. The method is linear from 0.1 to 15 microg/mL and 0.2 to 7 microg/mL for levofloxacin and moxifloxacin, respectively, covering the clinically relevant plasma concentration range. The limits of quantitation are 0.05 microg/mL (levofloxacin) and 0.2 microg/mL (moxifloxacin). The method is successfully applied to plasma drug level monitoring in a volunteer receiving single therapeutic doses of levofloxacin or moxifloxacin at two different occasions.
INTRODUCTION:Cardiotoxicity is a well-known complication of anthracycline chemotherapy. The incidence has been reported as high as 9% in solid cancer patients and up to 18% in acute myeloid leukemia (AML) patients [1].Unfortunately, anthracycline-induced cardiotoxicity (AIC) in AML patients represents a unique and high-risk subset of patients that are largely underrepresented in the literature.We report a case of a patient with AML who was admitted for induction chemotherapy with Cytarabine and Daunorubicin. Two weeks later she developed cardiogenic shock and was transferred to the ICU. A literature review reveals gaps in current research and suggests AML patients are at particularly high risk for developing AIC.CASE PRESENTATION: Ms. D was a 64 year-old female with AML admitted for induction chemotherapy with high dose Cytarabine and Daunorubicin. Eighteen days after receiving treatment she developed hypoxic respiratory failure with pulmonary edema and an echocardiogram showed a newly reduced ejection fraction of 30%. Heart catheterization revealed a depressed cardiac index. She was started on inotropic support with improved lactate clearance and cardiac function; however, given her poor overall prognosis, she was determined to not be a candidate for mechanical circulatory support. Congruent with the patient's wishes, she was placed on comfort measures and died 12 hours later. DISCUSSION: AIC is generally defined as >10% reduction in left ventricular ejection fraction (LVEF) with a final LVEF < 50% [2]. Pathogenesis is multifactorial and involves reactive oxygen species generation and defective mitochondrial biogenesis with a predilection for cardiac myocytes due to their high mitochondrial content [3]. Patient risk factors for AIC include age >65 or <18 years old, female sex, pre-existing cardiac disease and genetic factors [1]. In studies of solid cancer and lymphoma regimens, AIC is dose-dependent [1]. For unclear reasons, AML patients seem to experience unexpectedly high rates of AIC after induction. Medications to reduce the risk of AIC include chelation therapy with dexrazoxane, prolonged infusion times, liposomal preparations and pre-treatment with enalapril and carvedilol [3]. These interventions have failed to show consistent benefit in AML patients [1]. CONCLUSIONS:We present a case of AIC in an AML patient who's only known risk factor was female sex. This case and review of the literature suggests that AML patients are at an increased risk for developing AIC. More research is needed to determine effective preventative strategies for AML patients receiving anthracycline chemotherapy.
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