Clonal and subclonal TP53 molecular impairment is associated with prognosis and progression in multiple myeloma.

Aberrations on TP53, either as deletions of chromosome 17p (del17p) or mutations, are associated with poor outcome in multiple myeloma (MM), but conventional detection methods currently in use underestimate their incidence, hindering an optimal risk assessment and prognostication of MM patients. We have investigated the altered status of TP53 gene by SNPs array and sequencing techniques in a homogenous cohort of 143 newly diagnosed MM patients, evaluated both at diagnosis and at first relapse: single-hit on TP53 gene, either deletion or mutation, detected both at clonal and sub-clonal level, had a minor effect on outcomes. Conversely, the coexistence of both TP53 deletion and mutation, which defined the so-called double-hit patients, was associated with the worst clinical outcome (PFS: HR 3.34 [95% CI: 1.37-8.12] p = 0.008; OS: HR 3.47 [95% CI: 1.18-10.24] p = 0.02). Moreover, the analysis of longitudinal samples pointed out that TP53 allelic status might increase during the disease course. Notably, the acquisition of TP53 alterations at relapse dramatically worsened the clinical course of patients. Overall, our analyses showed these techniques to be highly sensitive to identify TP53 aberrations at sub-clonal level, emphasizing the poor prognosis associated with double-hit MM patients.

Opposite activation of the Hedgehog pathway in CD138+ plasma cells and CD138-CD19+ B cells identifies two subgroups of patients with multiple myeloma and different prognosis.

Hyperactivation of the Hedgehog (Hh) pathway, which controls refueling of multiple myeloma (MM) clones, might be critical to disease recurrence. Although several studies suggest the Hh pathway is activated in CD138- immature cells, differentiated CD138+ plasma cells might also be able to self-renew by producing themselves the Hh ligands. We studied the gene expression profiles of 126 newly diagnosed MM patients analyzed in both the CD138+ plasma cell fraction and CD138-CD19+ B-cell compartment. Results demonstrated that an Hh-gene signature was able to cluster patients in two subgroups characterized by the opposite Hh pathway expression in mature plasma cells and their precursors. Strikingly, patients characterized by Hh hyperactivation in plasma cells, but not in their B cells, displayed high genomic instability and an unfavorable outcome in terms of shorter progression-free survival (hazard ratio: 1.92; 95% confidence interval: 1.19-3.07) and overall survival (hazard ratio: 2.61; 95% confidence interval: 1.26-5.38). These results suggest that the mechanisms triggered by the Hh pathway ultimately led to identify a more indolent vs a more aggressive biological and clinical subtype of MM. Therefore, patient stratification according to their molecular background might help the fine-tuning of future clinical and therapeutic studies.

18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease.

Identification of patient sub-groups with smoldering multiple myeloma (SMM) at high risk of progression to active disease (MM) is an important goal. 18F-FDG PET/CT (positron emission tomography (PET) integrated with computed tomography (PET/CT) using glucose labelled with the positron-emitting radionuclide (18)F) allows for assessing early skeletal involvement. Identification of osteolytic lesions by this technique has recently been incorporated into the updated International Myeloma Working Group criteria for MM diagnosis. However, no data are available regarding the impact of focal lesions (FLs) without underlying osteolysis on time to progression (TTP) to MM. We hence prospectively studied a cohort of 120 SMM patients with PET/CT. PET/CT was positive in 16% of patients (1 FL: 8, 2 FLs: 3, >3 FLs: 6, diffuse bone marrow involvement: 2). With a median follow-up of 2.2 years, 38% of patients progressed to MM, in a median time of 4 years, including 21% with skeletal involvement. The risk of progression of those with positive PET/CT was 3.00 (95% confidence interval 1.58-5.69, P=0.001), with a median TTP of 1.1 versus 4.5 years for PET/CT-negative patients. The probability of progression within 2 years was 58% for positive versus 33% for negative patients. In conclusion, PET/CT positivity significantly increased the risk of progression of SMM to MM. PET/CT could become a new tool to define high-risk SMM.

Epilepsy and argininosuccinic aciduria.

BACKGROUND: We have reviewed the occurrence of epilepsy in our patients with argininosuccinic aciduria (ASA) (OMIM 207900) and the possible relationship of late epilepsy to symptomatic seizures in the neonatal period, hyperammonaemia and treatments. METHODS: We retrospectively analysed 11 ASA patients (8 neonatal onset and 3 late onset), 6 of whom had developed epilepsy. RESULTS: Epilepsy in our sample was frequent (55 %). It developed after a seizure-free period from the onset of the metabolic disease and seizures were responsive to treatment in all cases. Arginine plasma levels were kept in the same range for the 2 groups of patients with and without epilepsy. CONCLUSIONS: Although epilepsy is reported to be common among patients with ASA, very few long-term follow-up studies are available. The pathophysiological mechanism of epileptogenesis remains unclear. Neither hyperammonaemia nor acute symptomatic seizures at birth seem to be predictive of late epilepsy. Excessive arginine dosages as a cause of epilepsy could be reasonably excluded since our 3 late onset patients developed epilepsy before the diagnosis of ASA, at a time when they were likely to be arginine deficient. Arginine deficiency may not be excluded as cause of epilepsy, but further studies are needed to define its role.

Working memory interference control deficit in children referred by teachers for ADHD symptoms.

It has been hypothesised that children with Attention Deficit/Hyperactivity Disorder (ADHD) present memory problems, including working memory deficits. This research is aimed at finding clearer evidence of a working memory deficit in these children. In the first study 22 children that had been referred by teachers as having ADHD symptoms were compared with a control group. Their performance on a listening span test, drawn up by De Beni, Palladino, Pazzaglia, and Cornoldi (1998), was investigated. In this task the subjects were asked to select the names of animals in word strings and to remember the last word in each string. In a second study, 34 children with ADHD symptoms and 50 control children were presented with a visuospatial working memory task mirroring the verbal task used in Study 1. In both studies, the children with ADHD symptoms had difficulty in remembering the last item in the string and had a higher number of intrusions when memorising items that were not in the final position. The results were interpreted that children with ADHD symptoms have working memory problems because they are not capable of suppressing information that initially has to be processed, and subsequently excluded from memory. This particular difficulty can be interpreted as an inhibitory processing deficit. The implications of the results in understanding learning difficulties in children with ADHD are discussed.

Long-lasting effects of (+/-)3,4-methylenedioxymethamphetamine (ecstasy) on serotonin system function in humans.

BACKGROUND: Fifteen (+/-)3,4-Methylenedioxymethamphetamine (MDMA) users, who did not show other drug dependencies or prolonged alcohol abuse, and 15 control subjects were included in the study. METHODS: Prolactin (PRL) and cortisol (CORT) responses to the serotonergic agonist d-fenfluramine (D-fen), clinical psychobehavioral changes, and psychometric measures were evaluated 3 weeks and then 12 months after MDMA discontinuation. RESULTS: MDMA users showed significantly reduced PRL and CORT responses in comparison with control subjects at 3 weeks (respectively, p < .001; p < .005). The responses of PRL to D-fen were unmodified at 12 months after prolonged abstinence and were significantly reduced in comparison with controls (p < .001). In contrast, CORT responses in MDMA users were restored after 12 months of abstinence, with significantly higher responses to D-fen, in comparison with 3-week responses (p < .05). MDMA users' high scores on the Novelty Seeking (NS) scale on the Tridimensional Personality Questionnaire (TPQ) appeared unchanged by long-term abstinence. In contrast, Buss Durkee Hostility Inventory (BDHI) (Buss and Durkee 1957) direct and guilt scores decreased significantly after 12 months of abstinence. PRL AUCs at 12 months were inversely correlated with the measures of MDMA exposure (r = -.538). CONCLUSIONS: Our data indicate long-lasting 5-HT system impairment in abstinent MDMA users although the hypothesis of serotonergic changes attributable to a premorbid condition cannot be excluded. CORT restored responses to D-fen at 12 months, and the correlation of neuroendocrine changes with MDMA exposure suggest that the neuroendocrine impairment may be due to a partially reversible neurotoxic action of MDMA on the human brain.

Neuroendocrine correlates of temperament traits in abstinent opiate addicts.

PURPOSE: Studies investigating temperament traits of drug abusers and their biological correlates have disclosed high rates of novelty seeking (NS) in opiate addicts, possibly based on dysfunctions of the dopaminergic (DA) system. The aims of the present study were to see whether or not the monoamine functions were impaired in detoxified addicts and whether or not these alterations were correlated with temperament traits, given the possibility that impairment of the biological and temperament parameters might be responsible for the development of addiction. METHODS: We have investigated the DA, serotonergic (5-HT), and noradrenergic (NE) functions in 22 abstinent heroin addicts and 22 healthy controls by challenging the monoamine systems with the DA agonist bromocriptine (brom), the 5-HT agonist D-fenfluramine (D-fen), and the NE agonist clonidine (clon), respectively. We examined the temperament traits by measuring NS, harm avoidance (HA), and reward dependence (RD) using the "Three-Dimensional Personality Questionnaire" (TPQ). RESULTS: Addicts showed higher than normal NS scores at TPQ blunted 5-HT function, and normal DA and NE activities, in response to the neuroendocrine challenges. NS correlated negatively with the DA function in both addicts and controls, and negatively with the 5-HT function only in addicts. HA correlated positively with 5-HT function in controls but not in addicts. IMPLICATIONS: The impairment in 5-HT function observed in heroin addicts and the changes in the biological correlates of temperamental traits could increase the proneness to addiction and possible comorbid psychiatric disorders.

GABAergic function in detoxified heroin addicts: relationship to anxiety disorders.

The function of the GABAergic system was examined in 20 subjects with heroin dependence and abuse, 2 months after detoxification, and in 10 healthy volunteers, by measuring the growth hormone (GH) response to a challenge with the GABA B receptor agonist baclofen. Ten heroin addicts had comorbid anxiety disorder (Group A), while the other ten had heroin addiction uncomplicated by Axis I and II psychopathologies (Group B). GH responses to baclofen stimulation of Group A patients were significantly blunted, while those of Group B subjects did not differ from responses of healthy volunteers. Our data show that the function of the GABAergic system is impaired only in heroin addicts with comorbid anxiety disorders (anxious cluster), suggesting that the GABA system is not persistently influenced by prolonged exposure to opioid receptor stimulation.