Genomic and transcriptomic profiles and in vitro resistance to mitoxantrone and idarubicin in pediatric acute leukemias.

BACKGROUND: A major problem in the treatment of leukemia is the development of drug resistance to chemotherapeutic agents. METHODS: To determine the ex vivo drug resistance profile to anthracyclines, an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) cytotoxicity assay was performed on mononuclear cells obtained from 155 patients with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML). Gene expression profiles (for 51 patients with ALL and 16 with AML) were prepared on the basis of cRNA hybridization to oligonucleotide arrays of the human genome (Affymetrix). Hierarchical clustering, assignment location and biological function were investigated during the correlation analysis for identified probe sets. Comparative genomic hybridization (CGH) array profiles (34 patients with ALL and 12 with AML) were prepared on the basis of DNA hybridization to oligonucleotide arrays of the human genome (Agilent). The validation of the array results was performed by a quantitative reverse transcriptase polymerase chain reaction. RESULTS: The collected expression and CGH microarray experiment results indicate that the ITGB2, SCL6A7, CASP1 and DUSP genes may comprise a resistance marker for acute leukemia cells correlated with anthracyclines. Moreover, there were also identified chromosome rearrangements associated with drug resistance, such as del5q32-35.3 and amp8p12-p11.21. Precise genes, as well as genome aberrations, might be classified as targets in therapy. CONCLUSIONS: In AML, the resistance of blasts to idarubicin and mitoxantrone may reflect an impaired integrin pathway. In ALL, the development of resistance is caused by the inhibition of B and T cell activation. Copyright © 2016 John Wiley & Sons, Ltd.

Fried frailty phenotype assessment components as applied to geriatric inpatients.

BACKGROUND: Management of geriatric patients would be simplified if a universally accepted definition of frailty for clinical use was defined. Among definitions of frailty, Fried frailty phenotype criteria constitute a common reference frame for many geriatric studies. However, this reference frame has been tested primarily in elderly patients presenting with relatively good health status. OBJECTIVE: The aim of this article was to assess the usefulness and limitations of Fried frailty phenotype criteria in geriatric inpatients, characterized by comorbidity and functional impairments, and to estimate the frailty phenotype prevalence in this group. PATIENTS AND METHODS: Five hundred consecutive patients of the university hospital subacute geriatric ward, aged 79.0±8.4 years (67% women and 33% men), participated in this cross-sectional study. Comprehensive geriatric assessment and Fried frailty phenotype component evaluation were performed in all patients. RESULTS: Multimorbidity (6.0±2.8 diseases) characterized our study group, with a wide range of clinical conditions and functional states (Barthel Index of Activities of Daily Living 72.2±28.2 and Mini-Mental State Examination 23.6±7.1 scores). All five Fried frailty components were assessed in 65% of patients (95% confidence interval [CI] =60.8-69.2) (diagnostic group). One or more components were not feasible to be assessed in 35% of the remaining patients (nondiagnostic group) because of lack of past patient's body mass control and/or cognitive or physical impairment. Patients from the nondiagnostic group, as compared to patients from the diagnostic group, presented with more advanced age, higher prevalence of dementia, lower prevalence of hypertension, lower systolic and diastolic blood pressure, body mass index, Mini-Mental State Examination and Barthel Index of Activities of Daily Living. Despite diagnostic limitations, we found ≥3 positive criteria (thus, frailty diagnosis) in 54.2% of the study group (95% CI =49.8-58.6), with prevalence from 31.7% in sexagenarians to 67.6% in nonagenarians. CONCLUSION: Fried frailty phenotype criteria seem useful for geriatric inpatient assessment, despite diagnostic limitations. High prevalence of frailty among geriatric inpatients suggests that evaluation for frailty should be considered a part of the comprehensive geriatric assessment.