Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia.

PURPOSE: t(12;21)(p13; q22), present in approximately 25% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients. EXPERIMENTAL DESIGN: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. RESULTS: A significant approximately 3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)- ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)- ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95% confidence interval (95% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL. CONCLUSION: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.     

Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia.

PURPOSE: Between September 1991 and May 1997, within the International Berlin-Frankfurt-Muenster Study Group (I-BFM-SG), a randomized study was performed aimed at assessing the efficacy of prolonged use of high-dose l-asparaginase (HD-l-ASP) during continuation therapy in children with standard risk (SR) acute lymphoblastic leukemia (ALL), treated with a reduced BFM-type chemotherapy. PATIENTS AND METHODS: The Italian, Dutch, and Hungarian groups participated in this study denominated IDH-ALL-91, and 494 children were enrolled. Treatment consisted of a BFM-type modified backbone with omission of the IB part in induction and elimination of two doses of anthracyclines during reinduction in both arms at the beginning of continuation therapy. Patients were randomly assigned to receive (YES-ASP) or not (NO-ASP) 20 weekly HD-l-ASP (25,000 IU/m2). RESULTS: The event-free-survival and overall survival probabilities at 10 years for the entire group were 82.5% (1.8) and 90.3% (1.3), respectively. Of the 490 patients eligible for random assignment, 355 (72.4%) were randomly assigned (178 YES-ASP and 177 NO-ASP). After a median follow-up of 9 years, the probability of disease-free survival at 10 years was 87.5% (SE, 2.5) for YES-ASP arm versus 78.7% (SE, 3.3) for NO-ASP arm (P = .03). In multivariate analysis, NO-ASP arm (P = .03), male sex (P = .004), and age older than 10 years (P = .0003) had a significantly adverse impact on outcome. CONCLUSION: In this subset of patients, selected with criteria not including monitoring of minimal residual disease, application of extended HD-l-ASP may improve prognosis, compensating reduced leukemia control that results from adoption of a reduced-intensity BFM-backbone for treatment of children with SR ALL.     

Intermediate hypocretin-1 cerebrospinal fluid levels and typical cataplexy: their significance in the diagnosis of narcolepsy type 1

Study ObjectivesThe diagnosis of narcolepsy type 1 (NT1) is based upon the presence of cataplexy and/or a cerebrospinal fluid (CSF) hypocretin-1/orexin-A level ≤ 110 pg/mL. We determined the clinical and diagnostic characteristics of patients with intermediate hypocretin-1 levels (111–200 pg/mL) and the diagnostic value of cataplexy characteristics in individuals with central disorders of hypersomnolence.MethodsRetrospective cross-sectional study of 355 people with known CSF hypocretin-1 levels who visited specialized Sleep-Wake Centers in the Netherlands. For n = 271, we had full data on cataplexy type (“typical” or “atypical” cataplexy).ResultsCompared to those with normal hypocretin-1 levels (>200 pg/mL), a higher percentage of individuals with intermediate hypocretin-1 levels had typical cataplexy (75% or 12/16 vs 9% or 8/88, p < .05), and/or met the diagnostic polysomnographic (PSG) and Multiple Sleep Latency Test (MSLT) criteria for narcolepsy (50 vs 6%, p < .001). Of those with typical cataplexy, 88% had low, 7% intermediate, and 5% normal hypocretin-1 levels (p < .001). Atypical cataplexy was also associated with hypocretin deficiency but to a lesser extent. A hypocretin-1 cutoff of 150 pg/mL best predicted the presence of typical cataplexy and/or positive PSG and MSLT findings.ConclusionIndividuals with intermediate hypocretin-1 levels or typical cataplexy more often have outcomes fitting the PSG and MSLT criteria for narcolepsy than those with normal levels or atypical cataplexy. In addition, typical cataplexy has a much stronger association with hypocretin-1 deficiency than atypical cataplexy. We suggest increasing the NT1 diagnostic hypocretin-1 cutoff and adding the presence of clearly defined typical cataplexy to the diagnostic criteria of NT1. Clinical trial information: This study is not registered in a clinical trial register, as it has a retrospective database design.     

Effectiveness of averaging strategies to reduce variance in retinal nerve fibre layer thickness measurements using spectral-domain optical coherence tomography

Background

Automated detection of subtle changes in peripapillary retinal nerve fibre layer thickness (RNFLT) over time using optical coherence tomography (OCT) is limited by inherent image quality before layer segmentation, stabilization of the scan on the peripapillary retina and its precise placement on repeated scans. The present study evaluates image quality and reproducibility of spectral domain (SD)-OCT comparing different rates of automatic real-time tracking (ART).

Methods

Peripapillary RNFLT was measured in 40 healthy eyes on six different days using SD-OCT with an eye-tracking system. Image brightness of OCT with unaveraged single frame B-scans was compared to images using ART of 16 B-scans and 100 averaged frames. Short-term and day-to-day reproducibility was evaluated by calculation of intraindividual coefficients of variation (CV) and intraclass correlation coefficients (ICC) for single measurements as well as for seven repeated measurements per study day.

Results

Image brightness, short-term reproducibility, and day-to-day reproducibility were significantly improved using ART of 100 frames compared to one and 16 frames. Short-term CV was reduced from 0.94?±?0.31 % and 0.91?±?0.54 % in scans of one and 16 frames to 0.56?±?0.42 % in scans of 100 averaged frames (P?≤?0.003 each). Day-to-day CV was reduced from 0.98?±?0.86 % and 0.78?±?0.56 % to 0.53?±?0.43 % (P?≤?0.022 each). The range of ICC was 0.94 to 0.99. Sample size calculations for detecting changes of RNFLT over time in the range of 2 to 5 μm were performed based on intraindividual variability.

Conclusion

Image quality and reproducibility of mean peripapillary RNFLT measurements using SD-OCT is improved by averaging OCT images with eye-tracking compared to unaveraged single frame images. Further improvement is achieved by increasing the amount of frames per measurement, and by averaging values of repeated measurements per session. These strategies may allow a more accurate evaluation of RNFLT reduction in clinical trials observing optic nerve degeneration.     

Continuous infusion of low-dose doxorubicin, epirubicin and mitoxantrone in cancer chemotherapy: A review

With the recent development of reliable portable pumps and safe venous access systems, continuous infusion of chemotherapeutic agents on an out-patient basis has become feasible. Advantages of continuous infusion are the long-term exposure of tumour cells to the drug and the fact that most toxic effects are reduced for doxorubicin, epirubicin and mitoxantrone due to elimination of the high peak plasma levels. Preliminary data for doxorubicin suggest that its antitumour activity is maintained. Pharmacokinetic studies with epirubicin and mitoxantrone showed a linear relationship between drug dose infused and the steady-state plasma level for these drugs. The area under the curve for leukocytes drug level was higher during continuous infusion than after an equitoxic bolus injection of epirubicin and mitoxantrone. Well-randomized clinical trials will be necessary to investigate the role of continuous infusion of antracyclines and mitoxantrone in cancer chemotherapy in the future.     

The Five Factor Model of personality applied to adults who stutter

Previous research has not explored the Five Factor Model of personality among adults who stutter. Therefore, the present study investigated the five personality domains of Neuroticism, Extraversion, Openness, Agreeableness and Conscientiousness, as measured by the NEO Five Factor Inventory (NEO-FFI), in a sample of 93 adults seeking speech treatment for stuttering, and compared these scores with normative data from an Australian and a United States sample. Results revealed that NEO-FFI scores for the stuttering group were within the ‘average’ range for all five personality domains. However, adults who stutter were characterized by significantly higher Neuroticism, and significantly lower Agreeableness and Conscientiousness, than normative samples. No significant differences were found between groups on the dimensions of Extraversion and Openness. These results are discussed with reference to the relationship between personality factors among adults who stutter, their directionality, and implications for predicting treatment outcome.Learning outcomes: The reader will be able to: (1) describe the Five Factor Model of personality, including the NEO-FFI personality domains of Extraversion, Neuroticism, Openness, Agreeableness, and Conscientiousness, and (2) discuss differences in NEO-FFI domain scores between adults who stutter and normative samples, and (3) understand the clinical implications of personality profiles in terms of treatment process and outcome for adults who stutter.