Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia

Mutations in the all-trans retinoic acid (ATRA)-targeted ligand binding domain of PML-RARα (PRα/LBD(+)) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD(+) (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD(+). Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD(+)), which were differentially associated with PRα/LBD(+) depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD(+) were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD(+), high, S-isoform. These exploratory results suggest that differing PRα/LBD(+) activities may interact with FLT3-ITD(+) or ACA, that FLT3-ITD(+) and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD(+) were also associated with reduced postrelapse survival.     

Unintended Consequences of Implementing a National Performance Measurement System into Local Practice

BACKGROUND  

Although benefits of performance measurement (PM) systems have been well documented, there is little research on negative unintended consequences of performance measurement systems in primary care. To optimize PM systems, a better understanding is needed of the types of negative unintended consequences that occur and of their causal antecedents.     

Dopaminergic Function in the Psychosis Spectrum: An [18F]-DOPA Imaging Study in Healthy Individuals With Auditory Hallucinations

Background: The psychosis phenotype appears to exist in the population as a continuum, but it is not clear if subclinical psychotic symptoms and psychotic disorders share the same neurobiology. We investigated whether the dopaminergic dysfunction seen in psychotic disorders is also present in healthy, well-functioning people with hallucinations. Methods: We compared dopamine synthesis capacity (using 6-[¹⁸F]fluoro-L-DOPA [[¹⁸F]-DOPA] positron emission tomography imaging) in 16 healthy individuals with frequent persistent auditory verbal hallucinations (hallucinating group) with that in 16 matched controls. Results: There was no significant difference in dopamine synthesis capacity in the striatum, or its functional subdivisions, between groups and no relationship between subclinical psychotic symptom severity or schizotypal traits and dopamine synthesis capacity in the hallucinating group. Conclusions: Altered dopamine synthesis capacity is unlikely to underlie subclinical hallucinations, suggesting that although there may be a phenomenological psychosis continuum, there are distinctions at the neurobiological level.     

Exercise during energy restriction mitigates bone loss but not alterations in estrogen status or metabolic hormones

Summary

Energy restriction causes bone loss, increasing stress fracture risk. The impact of exercise during energy restriction on bone and endocrine factors is examined. Exercise with energy restriction did not influence endocrine factors, but did mitigate some bone loss seen with energy restriction in sedentary rats.

Introduction

Chronic dietary energy restriction (ER) leads to bone loss and increased fracture risk. Strictly controlled trials of long-term ER with and without vigorous exercise are required to determine whether exercise loading can counterbalance ER-induced bone loss. The aim of this current project is to elucidate the impact of exercise and ER on bone mass, estrogen status, and metabolic hormones.

Methods

Twenty-four virgin female Sprague-Dawley rats (n?=?8/group) were divided into three groups—ad libitum fed?+?exercise (Adlib?+?EX), 40 % energy restricted?+?exercise (ER?+?EX), and 40 % energy restricted?+?sedentary (ER?+?SED). Energy availability between ER groups was equal. Treadmill running was performed 4 days/week at 70 % VO_2max for 12 weeks.

Results

Fat and lean mass and areal bone mineral density (aBMD) were lower after 12 weeks (p?<?0.05) for ER?+?EX vs Adlib?+?EX, but ER?+?EX aBMD was higher than ER?+?SED (p?<?0.0001). Serum leptin and a urinary estrogen metabolite, estrone-1-glucuronide (E1G), were lower at week 12 (p?=?0.0002) with ER, with no impact of exercise. Serum insulin-like growth factor I (IGF-I) declined (p?=?0.02) from baseline to week 12 in both ER groups. ER?+?EX exhibited higher cortical volumetric bone mineral density (vBMD) at the midshaft tibia (p?=?0.006) vs ER?+?SED.

Conclusion

Exercise during ER mitigated some, but not all, of the bone loss observed in sedentary ER rats, but had little impact on changes in urinary E1G and serum IGF-I and leptin. These data highlight the importance of both adequate energy intake and the mechanical loading of exercise in maintaining bone mass.

     

Immunophenotyping in the diagnosis and classification of acute lymphoblastic leukemia

The identification of ALL immunophenotypes with distinctive clinical features and prognostic significance indicates the importance of these studies in the evaluation of ALL patients for both clinical and research purposes. For differential diagnosis, the expression of pan-B-cell or pan-T-cell lymphoid antigens and the absence of myeloid/monocyte antigens represent the most useful markers for distinguishing ALL from AML. However, the increasing appreciation of large numbers of patients with clinically significant mixed lymphoid-myeloid phenotypes suggests that rigid classification of acute leukemias into exclusive lymphoid and myeloid categories may be somewhat artificial. In adult ALL, patients with My+ phenotypes (B+sIg-T-My+ and B-sIg-T-My+) have a lower incidence of complete remission and shorter survival times than do patients with My- marker profiles. Preliminary studies in childhood ALL also suggest a correlation between myeloid antigen expression and poor prognostic factors. In addition, children with sIg+ "B-cell," cIg+ "pre-B-cell," and T-cell ALL phenotypes have shorter disease-free survival times than do patients with more common "early pre-B" (B+cIg-sIg-T-) marker profiles. Application of immunologic markers in concert with cytogenetic and gene rearrangement studies has led to the identification of novel subgroups of leukemia with distinct clinical characteristics. Future studies incorporating a multiparameter diagnostic approach including immunophenotyping, gene rearrangement studies, and karyotypic analyses should further our understanding of the heterogeneity of acute leukemias, guide the development of new therapeutic strategies, and provide for more clinically relevant classification of these disorders.     

The link between dopamine function and apathy in cannabis users: an [18F]-DOPA PET imaging study

Rationale

Cannabis is the most widely used illicit drug in the world, and regular use has been associated with reduced motivation, i.e. apathy. Regular long-term cannabis use has been associated with reduced dopamine synthesis capacity. The mesolimbic dopaminergic system mediates the processing of incentive stimuli by modifying their motivational value, which in turn is modulated by endocannabinoid signalling. Thus, it has been proposed that dopaminergic dysfunction underlies the apathy associated with chronic cannabis use.

Objectives

The aim of this study was to examine the relationship between dopaminergic function and subjective apathy in cannabis users.

Methods

We measured dopamine synthesis capacity (indexed as the influx rate constant K _i ^cer ) via 3,4-dihydroxy-6-[¹⁸F]-fluoro-l-phenylalanine positron emission tomography and subjective apathy using the self-rated Apathy Evaluation Scale (AES-S) in 14 regular cannabis users.

Results

All subjects scored in excess of 34 points on the AES-S (median [interquartile range] 59.5 [7.5]), indicative of significant apathy based on normative data. K _i ^cer was inversely correlated to AES-S score in the whole striatum and its associative functional subdivision (Spearman’s rho?=??0.64, p?=?0.015 [whole striatum]; rho?=??0.69, p?=?0.006 [associative]) but not in the limbic or sensorimotor striatal subdivisions. There were no significant relationships between AES-S and current cannabis consumption (rho?=?0.28, p?=?0.34) or age of first cannabis use (rho?=?0.25, p?=?0.40).

Conclusions

These findings indicate that the reduction in striatal dopamine synthesis capacity associated with chronic cannabis use may underlie reduced reward sensitivity and amotivation associated with chronic cannabis use.     

Chromosome abnormalities in peripheral T-cell lymphoma

We have studied neoplastic lymph nodes from six patients histologically, immunologically and cytogenetically. Histologically all the cases were classified as peripheral T-cell lymphomas. These were subclassified as T-zone lymphomas in three, large cell 'pale cell' variant in one, large cell immunoblastic in one, and small cell, mycosis fungoides in one. Two had features of angioimmunoblastic lymphadenopathy (AILD). Immunologically all cases expressed CD2 (OKT11) and CD4 (T4). All six cases had clonal chromosome abnormalities, although in four cases the majority of cells were chromosomally normal. Chromosome 3 was most often involved in abnormalities, occurring in five patients. The most common single chromosome abnormality, trisomy 3, was seen in all three cases classified as T-zone lymphoma and in no other cases. In the two cases with features of AILD only numerical abnormalities were seen, whereas in the other cases complicated structural rearrangements were present. Recurring structural abnormalities involved bands 1p12or13, 1q32, 3p25 and 14q11. Our data suggest that cytogenetic analysis may assist in diagnosis and classification of the peripheral T-cell lymphomas.