Valérie Lauwers-Cances

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.

Prevalence and risk factors for allergic contact dermatitis to topical treatment in atopic dermatitis: a study in 641 children

Background:  There is little information regarding the risk of sensitization associated with topical atopic dermatitis (AD) treatment.

Quantification of true in vivo (application) accuracy in cranial image-guided surgery: influence of mode of patient registration.

OBJECTIVE: Very few studies have attempted to quantify the true (application) accuracy of image-guidance systems during craniotomy. This is, in part, because of the lack of millimetric intraoperative targets to allow such measurements. Few in vivo studies have compared the influence of mode of patient registration on subsequent true accuracy. METHODS: Seven modes of patient registration (anatomic landmarks, 5 or 10 adhesive fiducials, bone-implanted fiducials [Stryker-Leibinger], surface matching using 45 or 100 points over scalp convexity or nose/auditory meatus contours) were compared. Thirty patients were involved in the study. Millimetric targets (bone drill holes or deep 1-mm titanium hemoclips) were placed then localized and saved at surgery. These targets were then identified on postoperative volumetric computed tomography fused with operative data sets. Localization errors of the targets were measured for each registration on an optical image-guidance system (StealthStation). RESULTS: Only implanted cranial fiducials had a statistically significant accuracy advantage (1.7 ± 0.7 mm). All other registrations had similar accuracies (approximately 4.0 ± 1.7 mm) except anatomic landmarks, which were worse (4.8 ± 1.9 mm). Calculated accuracies (root mean squared) had no predictive value for true (application) accuracies. CONCLUSION: Not surprisingly, application accuracy of image-guidance is worse without implanted cranial markers. Unexpectedly, there was no major difference in localization of deep targets between the other registrations tested in this study. Care must be taken when using image-guidance tools to consider error introduced by registration. Cranium-implanted fiducials should be considered when high accuracy and reproducibility are needed.

Reading abilities and cognitive functions of children with epilepsy: Influence of epileptic syndrome

Children with epilepsy are at risk of developing learning disorders. To explore the influence of the epileptic syndrome on reading abilities, we have compared the neuropsychological profile of 12 children with benign idiopathic epilepsy with rolandic spikes, 10 with temporal lobe epilepsy and 12 with idiopathic generalized epilepsy. Children underwent a selection of standardised tests designed to assess: oral language, reading, short-term memory, attention and behavioural adjustment. Analysis of variance was adjusted according to age of onset of the epileptic syndrome, duration of the syndrome, and performance IQ for each group. Children with temporal lobe epilepsy (TLE) had significantly lower scores for reading speed and comprehension, but epileptic variables (the age of onset of epilepsy, duration and activity of epilepsy) had influenced academic performances. In the TLE group there was a clear effect of the topography of the epileptic foci (left-side TLE vs. right-side TLE) on reading profile. Furthermore, the effect of epileptic syndromes was found in phonological, semantic and verbal working memory deficits in the TLE group. To a lesser extent children with idiopathic generalized epilepsy (IGE) also exhibit cognitive deficit. The results of the present study lend support to epilepsy-specific patterns of neuropsychological dysfunction in children that should be considered to improve remediation of academic underachievement in these populations.

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.

Characteristics of lung cancer in women: importance of hormonal and growth factors.

Based on epidemiological, clinical, and preclinical data, lung carcinogenesis can be distinctive in women, suggesting that women should be treated differently depending on the expression of various specific biomarkers. We aimed to describe the hormonal and genetic profile of lung cancer in both men and women to identify gender specificities. Primary lung-tumor tissues from surgically treated patients, (50 men, 50 women) were analyzed and compared for expression of estrogen receptors (ER) α and β, progesterone receptors (PR), epidermal growth-factor receptor (EGFR), and HER2 (for EGFR and K-Ras mutations). These data were combined with clinical and outcome data. Fewer women with lung cancer were smokers (p=0.001) and they smoked fewer cigarettes (p=0.001). We observed a higher rate of EGFR mutations (p=0.02) and ERα expression (p=0.006) in women. ERβ and EGFR were also expressed more frequently in women (p=0.29 and p=0.16). HER2 was overexpressed regardless of gender in three men and two women. K-Ras was mutated in 16% of both men and women. Interestingly, there was a positive link between EGFR expression and expression of ERα (p=0.028) and ERβ (p=0.047) in both men and women. Expression of ERα was associated with improved disease-free survival (p=0.007). Our findings provide further evidence on the specificities of lung cancer in women. The differential expression of specific biomarkers, which could be targeted by therapy, favors the development of gender-based treatment guided by biomarker expression.

Histological regression in primary melanoma: not a predictor of sentinel lymph node metastasis in a cohort of 397 patients

Background  Regression has been proposed as a potential marker of dissemination in thin melanomas. Previous studies have shown conflicting results.

Significant delay in the introduction of systemic treatment of moderate to severe psoriasis: a prospective multicentre observational study in outpatients from hospital dermatology departments in France

Background  There is a low rate of systemic treatment usage in moderate to severe psoriasis.

Basic Fibroblast Growth Factor-2/β3 Integrin Expression Profile: Signature of Local Progression After Chemoradiotherapy for Patients With Locally Advanced Non–Small-Cell Lung Cancer

PURPOSE No biologic signature of chemoradiotherapy sensitivity has been reported for patients with locally advanced non-small-cell lung cancer (NSCLC). We have previously demonstrated that basic fibroblast growth factor (FGF-2) and alphavbeta3 integrin pathways control tumor radioresistance. We investigated whether the expression of the proteins involved in these pathways might be associated with the response to treatment and, therefore, the clinical outcome. METHODS AND MATERIALS FGF-2, beta3 integrin, angiopoietin-2, and syndecan-1 expression was studied using immunohistochemistry performed on biopsies obtained, before any treatment, from 65 patients exclusively treated with chemoradiotherapy for locally advanced NSCLC. The response to treatment was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria using computed tomography at least 6 weeks after the end of the chemoradiotherapy. Local progression-free survival, metastasis-free survival, and disease-free survival were studied using the log-rank test and Cox proportional hazard analysis. RESULTS Among this NSCLC biopsy population, 43.7% overexpressed beta3 integrin (beta3(+)), 43% FGF-2 (FGF-2(+)), 41.5% syndecan-1, and 59.4% angiopoietin-2. Our results showed a strong association between FGF-2 and beta3 integrin expression (p = .001). The adjusted hazard ratio of local recurrence for FGF-2(+)/beta3(+) tumors compared with FGF-2(-)/beta3(-) tumors was 6.1 (95% confidence interval, 2.6-14.6, p = .005). However, the risk of local recurrence was not increased when tumors overexpressed beta3 integrin or FGF-2 alone. Moreover, the co-expression of these two proteins was marginally associated with the response to chemoradiotherapy and metastasis-free survival. CONCLUSION The results of this study have identified the combined profile FGF-2/beta3 integrin expression as a signature of local control in patients treated with chemoradiotherapy for locally advanced NSCLC.

Tipifarnib Plus Tamoxifen in Tamoxifen-Resistant Metastatic Breast Cancer: A Negative Phase II and Screening of Potential Therapeutic Markers by Proteomic Analysis

Purpose: Tipifarnib, a farnesyltransferase inhibitor, has antitumor activity in heavily pretreated metastatic breast cancer patients. Preclinical data suggest that FTIs could restore tamoxifen responsiveness in tamoxifen-resistant disease. Thus, combining FTIs and tamoxifen may be a promising clinical approach after relapse or progression on tamoxifen. Experimental Design: Postmenopausal patients with measurable estrogen receptor– and/or progesterone receptor–expressing metastatic breast cancers were enrolled. Only patients with disease progression on tamoxifen were eligible, but there was no limitation regarding prior chemotherapy or hormone therapy regimens. Patients were immediately treated with 300 mg (n = 12) or 200 mg (n = 10) tipifarnib twice daily for 21 of 28-day cycles plus tamoxifen once daily. Serum was collected at baseline and after 8 weeks of treatment to enable proteomic comparison and identify possible predictive response markers. Results: Twenty patients were enrolled and evaluated for efficacy: one patient had an objective response (liver metastasis) and nine had stable disease after 6 months for a clinical benefit rate of 50%; median duration of benefit was 10.3 (range, 7.4-20.2) months. The proteomic analysis by SELDI-TOF and LTQ-FT-Orbitrap identified a known peptide of fibrinogen α, the intensity of which was significantly increased in patients with progression compared with patients who benefited from the combined treatment after 8 weeks. Conclusions: Because the primary end point of efficacy (three objective responses) was not achieved, the study is negative. Nevertheless, the identified peptide could be of interest in discriminating, at 8 weeks of treatment, responders from nonresponders. Clin Cancer Res; 16(4); 1264–71