Catherine Gentil

Front-Line Transplantation Program With Lenalidomide, Bortezomib, and Dexamethasone Combination As Induction and Consolidation Followed by Lenalidomide Maintenance in Patients With Multiple Myeloma: A Phase II Study by the Intergroupe Francophone du Myélome

PURPOSE The three-drug combination of lenalidomide, bortezomib, and dexamethasone (RVD) has shown significant efficacy in multiple myeloma (MM). The Intergroupe Francophone du Myélome (IFM) decided to evaluate RVD induction and consolidation therapies in a sequential intensive strategy for previously untreated transplantation-eligible patients with MM. PATIENTS AND METHODS In this phase II study, 31 symptomatic patients age < 65 years were enrolled to receive three RVD induction cycles followed by cyclophosphamide harvest and transplantation. Patients subsequently received two RVD consolidation cycles and 1-year lenalidomide maintenance. RESULTS Very good partial response rate or better at the completion of induction, transplantation, and consolidation therapy was 58%, 70%, and 87%, respectively. Maintenance upgraded responses in 27% of patients. Overall, 58% of patients achieved complete response, and 68% were minimal residual disease (MRD) negative by flow cytometry. The most common toxicities with RVD were neurologic and hematologic, including grade 1 to 2 sensory neuropathy (55%), grade 3 to 4 neutropenia (35%), and thrombocytopenia (13%). Two basal cell carcinomas in the same patient and one case of breast cancer were observed. There was no treatment-related mortality. With a median follow-up of 39 months, estimated 3-year progression-free and overall survival were 77% and 100%, respectively. None of the patients who achieved MRD negativity relapsed. CONCLUSION The transplantation program with RVD induction and consolidation followed by lenalidomide maintenance produced high-quality responses and showed favorable tolerability in patients with newly diagnosed MM. Overall, 68% of patients achieved MRD negativity; none of these patients relapsed. This program is being evaluated in the ongoing IFM/Dana-Farber Cancer Institute 2009 phase III study.

DNA polymerase θ up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability

“Replicative stress” is one of the main factors underlying neoplasia from its early stages. Genes involved in DNA synthesis may therefore represent an underexplored source of potential prognostic markers for cancer. To this aim, we generated gene expression profiles from two independent cohorts (France, n = 206; United Kingdom, n = 117) of patients with previously untreated primary breast cancers. We report here that among the 13 human nuclear DNA polymerase genes, DNA Polymerase θ (POLQ) is the only one significantly up-regulated in breast cancer compared with normal breast tissues. Importantly, POLQ up-regulation significantly correlates with poor clinical outcome (4.3-fold increased risk of death in patients with high POLQ expression), and this correlation is independent of Cyclin E expression or the number of positive nodes, which are currently considered as markers for poor outcome. POLQ expression provides thus an additional indicator for the survival outcome of patients with high Cyclin E tumor expression or high number of positive lymph nodes. Furthermore, to decipher the molecular consequences of POLQ up-regulation in breast cancer, we generated human MRC5-SV cell lines that stably overexpress POLQ. Strong POLQ expression was directly associated with defective DNA replication fork progression and chromosomal damage. Therefore, POLQ overexpression may be a promising genetic instability and prognostic marker for breast cancer.

Chronic effects of shift work on cognition: findings from the VISAT longitudinal study

Objectives Shift work, like chronic jet lag, is known to disrupt workers’ normal circadian rhythms and social life, and to be associated with increased health problems (eg, ulcers, cardiovascular disease, metabolic syndrome, breast cancer, reproductive difficulties) and with acute effects on safety and productivity. However, very little is known about the long-term consequences of shift work on cognitive abilities. The aim of this study was to assess the chronicity and reversibility of the effects of shift work on cognition. Methods We conducted a prospective cohort study of 3232 employed and retired workers (participation rate: 76%) who were 32, 42, 52 and 62 years old at the time of the first measurement (t1, 1996), and who were seen again 5 (t2) and 10 (t3) years later. 1484 of them had shift work experience at baseline (current or past) and 1635 had not. The main outcome measures were tests of speed and memory, assessed at all three measurement times. Results Shift work was associated with impaired cognition. The association was stronger for exposure durations exceeding 10 years (dose effect; cognitive loss equivalent to 6.5 years of age-related decline in the current cohort). The recovery of cognitive functioning after having left shift work took at least 5 years (reversibility). Conclusions Shift work chronically impairs cognition, with potentially important safety consequences not only for the individuals concerned, but also for society.

Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer's disease

BackgroundThe accumulation of beta amyloid (Aβ) peptides, a hallmark of Alzheimer’s disease (AD) is related to mechanisms leading to neurodegeneration. Among its pleiotropic cellular effects, Aβ accumulation has been associated with a deregulation of sphingolipid metabolism. Sphingosine 1-phosphate (S1P) derived from sphingosine is emerging as a critical lipid mediator regulating various biological activities including cell proliferation, survival, migration, inflammation, or angiogenesis. S1P tissue level is low and kept under control through equilibrium between its synthesis mostly governed by sphingosine kinase-1 (SphK1) and its degradation by sphingosine 1-phosphate lyase (SPL). We have previously reported that Aβ peptides were able to decrease the activity of SphK1 in cell culture models, an effect that could be blocked by the prosurvival IGF-1/IGF-1R signaling.ResultsHerein, we report for the first time the expression of both SphK1 and SPL by immunohistochemistry in frontal and entorhinal cortices from 56 human AD brains. Immunohistochemical analysis revealed a decreased expression of SphK1 and an increased expression of SPL both correlated to amyloid deposits in the entorhinal cortex. Otherwise, analysis of brain tissue extracts showed a decrease of SphK1 expression in AD brains whereas SPL expression was increased. The content of IGF-1R, an activator of SphK1, was found decreased in AD brains as well as S1P1, the major receptor for S1P.ConclusionsCollectively, these results highlight the importance of S1P in AD suggesting the existence of a global deregulation of S1P signaling in this disease from its synthesis by SphK1 and degradation by SPL to its signaling by the S1P1 receptor.

Higher mental stimulation at work is associated with improved cognitive functioning in both young and older workers

The study examined whether mental stimulation received in the workplace positively affects cognitive functioning and rate of cognitive change. Data taken from the VISAT (ageing, health and work) longitudinal study concerned 3237 workers who were seen three times (in 1996, 2001 and 2006) and who were aged between 32 and 62 years at baseline. Measures of cognitive stimulation both at work and outside work were available at baseline. Cognitive efficiency was assessed on the three occasions through episodic verbal memory, attention and processing speed tests. Greater cognitive stimulation (at work and outside work) was associated with higher levels of cognitive functioning and a more favourable change over the 10-year follow-up. These results were obtained after adjustment for age, education, sex and a variety of medical, physical and psychosocial confounders. The study thus supports the hypothesis that exposure to jobs that are mentally demanding and that offer learning opportunities increases the level of cognitive functioning and possibly attenuates age-related decline. Statement of Relevance: The effect of occupational activity on cognitive functioning is under-researched. This paper reports results from a substantive longitudinal study, with findings indicating that exposure to jobs that are mentally demanding are beneficial in increasing levels of cognitive functioning and possibly attenuating age-related decline.

Searching for a relevant definition of sarcopenia: results from the cross‐sectional EPIDOS study

The diversity of definitions proposed for sarcopenia has been rarely tested in the same population, and so far, their clinical utilities for predicting physical difficulties could not be clearly understood. Our objective is to report the prevalence of sarcopenia and the characteristics of sarcopenic community‐dwelling older women according to the different definitions of sarcopenia currently proposed. We also assessed these definitions for their incremental predictive value over currently standard predictors for some self‐reported difficulties in physical function and knee extension strength.

Breslow Thickness, Clark Index and Ulceration Are Associated with Sentinel Lymph Node Metastasis in Melanoma Patients: A Cohort Analysis of 612 Patients

Background: Sentinel lymph node biopsy (SLNB) is the most sensitive procedure for assessing nodal status in patients with primary melanoma. Objective: To evaluate the predictive ability of usual primary melanoma prognosis factors of detecting sentinel lymph node (SLN) metastasis in patients with melanoma. Patients and Methods: A cohort of 612 consecutive patients presenting with primary skin melanoma who underwent a SLNB was evaluated. Assessment of the determinants of SLN metastasis was based on general linear model analysis. The model performance was studied using the concordance statistic and the net reclassification index. The calibration was estimated using the Hosmer-Lemeshow test. Results: The discrimination ability did not differ significantly between Breslow thickness (0.57), Clark index (0.61), ulceration (0.57) and histological subtype (0.55). Clark index, ulceration and Breslow thickness were all significant and independent determinants of SLN metastasis. The predictive ability of the final model was 0.657. Conclusion: Breslow thickness, Clark index and ulceration are independent predictors of a SLN metastasis.

Deficit in phonological processes: a characteristic of the neuropsychological profile of children with NF1

ABSTRACT Learning disabilities are one of the most frequent complications of neurofibromatosis type 1 (NF1) in children. Studies of the effects of the neurocognitive deficit on academic performance are relatively rare, owing to the small size of the populations concerned. However, research is needed to develop effective rehabilitation programs. In the present study, we explored the impact of a possible phonological deficit on the reading abilities of children with NF1. A multicenter, cross-sectional study was conducted in France on two groups of 75 children with or without NF1 aged 8–12 years, matched for age, sex, handedness, and reading level. All participants underwent a neuropsychological evaluation to assess their general cognitive level, reading skills, phonological processes, visuoperceptual abilities, and attentional capacity. Phonological skills were assessed by means of two phonological awareness tasks and one short-term memory task. In the group of children with NF1, 41% had reading difficulties. Phonological processes were impaired in this group, compared with the children without NF1. Similar differences were found for a phoneme deletion task after adjustment for reading difficulties, IQ level, and visuoperceptual abilities. Phonological awareness, but not phonological short-term memory, was impaired in children with NF1, and not just those whose reading was impaired. Results suggest that children with NF1 have a phonological awareness deficit, whatever their reading level. Identification of reduced phonological skills may warrant the implementation of a specific rehabilitation program before early reading difficulties emerge.

Author response to “Time of day of cognitive tests might distort shift-work study results”

Holt suggests that the shift workers in our study1 may have been performing worse than day workers because they performed the tests during their ‘biological night’ (ie, during the day). It is indeed the case that the cognitive tests were administered during the day, but the available evidence suggests that even the vast majority (>95%) of permanent night workers fail to …