Minimal residual disease-based treatment is adequate for relapse-prone childhood acute lymphoblastic leukemia with an intrachromosomal amplification of chromosome 21: the experience of the ALL-BFM 2000 trial.

BACKGROUND: Recently, the UK CCLG and COG reported that an intrachromosomal amplification of chromosome 21 (iAMP21) in acute lymphoblastic leukemia (ALL) loses its adverse prognostic impact with intensified therapy. PATIENT AND METHODS: We evaluated the prognosis of iAMP21 among patients from the ALL-BFM (Berlin-Frankfurt-Münster) 2000 trial with 46 of 2 637 (2%) patients iAMP21+. RESULTS: 8-year event-free-survival (EFS, 64 ± 8% vs. 81 ± 1%, p=0.0026) and cumulative incidence of relapse (CIR, 29 ± 8% vs. 14 ± 1%, p=0.008) of the iAMP21 cases were significantly worse compared with non-iAMP21 patients. Within the MRD low-risk group, iAMP21 cases (n=14) had an inferior 8-year EFS (76 ± 12% vs. 92 ± 1%, p=0.0081), but no increased CIR (10 ± 10% vs. 6 ± 1%, p=0.624). Within the MRD intermediate-risk group, iAMP21 cases (n=27) had a worse 8-year EFS (56 ± 11% vs. 78 ± 2%, p=0.0077) and CIR (44 ± 11% vs. 20 ± 2%, p=0.003) with 6/10 relapses occurring after 2 years. CONCLUSIONS: Conclusively, we believe that there is no necessity for enrolling all iAMP21 patients into the high-risk arm of ongoing ALL-BFM trials because MRD low-risk patients have a moderate relapse risk under current therapy. Whether the increased relapse risk in MRD intermediate-risk patients can be avoided by late treatment intensification remains to be answered by the AIEOP-BFM ALL 2009 trial randomly using protracted pegylated L-asparaginase during delayed intensification and early maintenance.

Veterinary Students' Sense of Belonging: Growing Community with Small Group Academic Enhancement.

A student's sense of belonging to a university is associated with success in academic setting, happiness, and satisfaction. It is therefore unsurprising that universities commonly strive to improve student measures of belonging especially considering its negative correlation with attrition rates. This study documents the implementation and assessment of a new curricular intervention at Ross University School of Veterinary Medicine (RUSVM) and measures associated changes in students' feeling of belonging to the university and accountability for their success. Specifically, small, group, faculty-guided weekly discussion sessions were introduced to the Veterinary Professional Foundation (VPF) course to complement a series of updated didactic only lectures. Voluntary surveys ("belonging to the university scale" [1] and the "personal accountability in education scale" [2]) were utilized to document student attitudes and feelings surrounding these variables. Likert scores from a control group of students who completed the VPF course prior to the curricular change were compared to the intervention group who engaged in the weekly guided discussion sessions via a Wilcoxon test. The intervention group reported significantly improved feelings of belonging to the university (p-values ranging from 0.008 to 0.027). Minimal change was noted between groups associated with accountability. The addition of weekly small group meetings has proven valuable at RUSVM in improving student sense of belonging to the university. Further research is indicated to determine if accountability may be improved over a longer period of monitoring with continued interventions.

Genotype-outcome correlations in pediatric AML: the impact of a monosomal karyotype in trial AML-BFM 2004.

We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of specific chromosomal aberrations including monosomal (MK+), complex (CK+) and hypodiploid (HK+) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK+ (n=22) as a new independent risk factor for poor event-free survival (EFS 23±9% vs 53±2% for all other patients, P=0.0003), even after exclusion of four patients with monosomy 7 (EFS 28±11%, P=0.0081). CK+ patients without MK had a better prognosis (n=47, EFS 47±8%, P=0.46) than those with MK+ (n=12, EFS 25±13%, P=0.024). HK+ (n=37, EFS 44±8% for total cohort, P=0.3) influenced outcome only when t(8;21) patients were excluded (remaining n=16, EFS 9±8%, P<0.0001). An extremely poor outcome was observed for MK+/HK+ patients (n=10, EFS 10±10%, P<0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n=16, EFS 25±11%, P=0.0091). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.

Influence of exogenous melatonin on melatonin secretion and the neuroendocrine reproductive axis of intact male rats during sexual maturation.

The influence of daily sc administration of melatonin (5-100 micrograms/day) on sexual development of prepubertal and pubertal male rats was studied in vivo. Adult animals were also studied. When melatonin was injected daily into young animals starting at day 20 of age, dose-dependent reductions in plasma testosterone, testis and seminal vesicles weights, plasma FSH and LH levels, and pituitary GnRH receptor number were observed at day 40 or 45 of age when animals were killed. In contrast, prepubertal animals (5-20 days old) showed no significant responses to similar treatment with melatonin, whereas in adult animals (70-90 days old), melatonin elicited only a small decrease in plasma testosterone concentration. Melatonin analogs such as N-acetyl-serotonin and 5-hydroxytryptophol administered daily from 20-45 days of age did not produce any effect. Chronic melatonin administration from 20-50 days of life did not alter the occurrence of the nocturnal rise of circulating plasma melatonin, but did enhance its amplitude. Our results demonstrate that exogenous melatonin can inhibit or delay sexual maturation in the male rat if administered between 20 and 40 days of age and suggest that this inhibitory action is exerted at the hypothalamic and/or pituitary level.

Daily afternoon administration of melatonin does not irreversibly inhibit sexual maturation in the male rat.

Previous studies from our laboratory demonstrated that daily afternoon melatonin injections from 20-40 days of age inhibited sexual development of young male rats, whereas in adult animals, similar injections had no effect. The present study was designed to determine more precisely the critical age period during which melatonin exerts its inhibiting effect and to see whether spontaneous sexual maturation resumes after discontinuation of melatonin administration at 45 days of age or even during continuous administration of melatonin until 115 days of age. Sexual maturation was evaluated using weights of seminal vesicles and testes; plasma levels of testosterone, FSH, and LH; pituitary contents and concentrations of FSH and LH; and, finally, pituitary content of GnRH receptors. Administration of melatonin to young male rats from 20-30 days of life had the same inhibitory effect on sexual maturation at 40 days as melatonin injections from 20-40 days. In contrast, administration of melatonin from 30-40 days only slightly decreased plasma testosterone concentration, weight of seminal vesicles, and pituitary GnRH receptor content. Melatonin administration from 38-40 days had no effect. Daily melatonin administration from 20-45 days of age was followed by resumption of sexual maturation, as observed at 70 days. The recovery was complete by 80 days of age when all of the parameters studied reflected complete sexual maturation. Finally, in rats treated continuously with melatonin from days 20 until 115, sexual maturation occurred but was delayed by about 20-30 days. Beginning of sexual development was observed at 60 days of life, and full development was attained only at 100 days. These data confirm that melatonin delays sexual maturation in the young male rat when administered daily in the afternoon. They demonstrate that this inhibitory action of melatonin is most critical between 20 and 30 days of life and is reversible regardless of whether melatonin administration is discontinued after 45 days of life. The suppression of the pubertal peaks of pituitary GnRH receptor number and pituitary and plasma FSH concentrations in treated rats suggests that melatonin interferes with the pubertal increase in GnRH secretion. In conclusion, these reversible effects of melatonin suggest that this pineal indolamine represents an important factor for the timing of sexual maturation.

Long-term studies on immunoreactive human melatonin.

Immunoreactive melatonin has been studied in normal human volunteers, both men and women, at different times of day and different times of the year. At 2400, but not at 0800 or 1200, there are very large inter-individual variations in mean levels, the maximum difference being fivefold. Intra-individual variations are seen at different times of the year at 2400 and 0800, with low values in spring and autumn and high values in summer and winter.

Diurnal rhythm of melatonin action on sexual maturation of male rats.

Immature male Wistar rats with a 12:12 h light-dark cycle received daily s.c. melatonin injections of 100 micrograms from 20 to 40 days of age. Melatonin administration during the late photophase (9 h after the onset of light) or during the late scotophase (9 h after the onset of darkness) caused reduced weights of testes and seminal vesicles, lowered plasma levels of testosterone, LH and FSH, and decreased number of pituitary GnRH receptors, a series of observations which reflects delayed sexual maturation at 40 days. In contrast, no effect was observed when melatonin was injected during the early photophase of scotophase (5 h after the onset of light or darkness, respectively). In order to better investigate the night hours, melatonin action was studied in rats that were born and raised with a shifted 12:12 h light-dark cycle. When the light phase was shifted by 5 and 17 h 1 week before the animals were born, sensitivity to melatonin action was unchanged. The responsiveness of the neuroendocrine-reproductive axis to exogenous melatonin was then studied throughout the day-night cycle. The inhibitory influence of melatonin increased gradually during the late photophase and reached a peak just before the onset of darkness. No effect was observed during the first 7 h of the dark phase; however, melatonin injected 9 h after the onset of darkness again had an inhibitory influence equivalent to about 50% of that observed in the late photophase , whereas administration 2 h later remained without effect. These results demonstrate that the time of administration of melatonin within the day-night cycle is critical for melatonin action.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory action of exogenous melatonin, 5-methoxytryptamine, and 6-hydroxymelatonin on sexual maturation of male rats: activity of 5-methoxytryptamine might be due to its conversion to melatonin.

The effect on sexual maturation of 6 different pineal indoles, including melatonin, and of the metabolite 6-hydroxymelatonin was studied in the male rat after daily injections from 20 to 40 days of age. Only 5-methoxytryptamine (5MT) and 6-hydroxymelatonin (6M), in addition to melatonin, inhibited the neuroendocrine-reproductive axis during sexual maturation. Their potencies when injected in the afternoon were in the range of one-twentieth to one-fifth that of melatonin. Like melatonin these two indoles had no effect when injected in the morning. N-acetylserotonin, serotonin, 5-hydroxytryptophol and 5-methoxytryptophol did not influence sexual maturation either when injected in the morning or in the afternoon. Chromatographic separation was performed on plasma extracts from rats injected daily with the biologically active indoles and killed 10-120 min after the last injection. This procedure confirmed that 6M injections did not increase plasma melatonin levels. In contrast, plasma melatonin levels in 5MT-treated rats were increased 1 h after the 5MT injection. These results suggest that 5MT or part of it might be acetylated to melatonin; thus inhibition of sexual maturation might be mainly due to melatonin. These results indirectly support the contention that melatonin is the principal pineal indoleamine playing a role during sexual maturation.