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Since its publication in 2013, the Visual Communication and Sign Language (VCSL) Checklist has been widely utilized to assess the development of early American Sign Language skills of deaf children from birth to age 5. However, little research has been published using the results of VCSL assessments. Notably, no psychometric analyses have been conducted to verify the validity of the VCSL in a population whose characteristics are different from those of the small sample of native signing children from whom the published norms were created. The current paper, using data from the online version of the VCSL (VCSL:O), addresses this shortcoming. Ratings of the 114 VCSL items from 562 evaluations were analyzed using a partial-credit Rasch model. Results indicate that the underlying skill across the age range comprises an adequate single dimension. Within the items’ age groupings, however, the dimensionality is not so clear. Item ordering, as well as item fit, is explored in detail. In addition, the paper reports the benefits of using the resulting Rasch scale scores, which, unlike the published scoring strategy that focuses on basal and ceiling performance, makes use of the ratings of partial credit, or emerging, skills. Strategies for revising the VCSL are recommended.

The STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is of utmost importance notably towards personalized medicine treatments against diseases such as viral infections (COVID-19, Dengue…), cancers, or auto-inflammatory diseases. Owing to micro-seconds scale molecular modeling simulations and post-processing by contacts analysis and Machine Learning techniques, we reveal the dynamical behavior of four STING variants (wild type, G230A, R293Q, and G230A-R293Q) and we rationalize the variability of efficiency observed experimentally. Our results show that the decrease of STING activity is linked to a stiffening of key-structural features of the binding cavity, together with changes of the interaction patterns within the protein.

Background Transfemoral amputation is a serious intervention that alters the locomotion pattern, leading to secondary disorders and reduced quality of life. The outcomes of current gait rehabilitation for TFAs seem to be highly dependent on factors such as the duration and intensity of the treatment and the age or etiology of the patient. Although the use of robotic assistance for prosthetic gait rehabilitation has been limited, robotic technologies have demonstrated positive rehabilitative effects for other mobility disorders and may thus offer a promising solution for the restoration of healthy gait in TFAs. This study therefore explored the feasibility of using a bilateral powered hip orthosis (APO) to train the gait of community-ambulating TFAs and the effects on their walking abilities. Methods Seven participants (46–71 years old with different mobility levels) were included in the study and assigned to one of two groups (namely Symmetry and Speed groups) according to their prosthesis type, mobility level, and prior experience with the exoskeleton. Each participant engaged in a maximum of 12 sessions, divided into one Enrollment session, one Tuning session, two Assessment sessions (conducted before and after the training program), and eight Training sessions, each consisting of 20 minutes of robotically assisted overground walking combined with additional tasks. The two groups were assisted by different torque-phase profiles, aiming at improving symmetry for the Symmetry group and at maximizing the net power transferred by the APO for the Speed group. During the Assessment sessions, participants performed two 6-min walking tests (6mWTs), one with (Exo) and one without (NoExo) the exoskeleton, at either maximal (Symmetry group) or self-selected (Speed group) speed. Spatio-temporal gait parameters were recorded by commercial measurement equipment as well as by the APO sensors, and metabolic efficiency was estimated via the Cost of Transport (CoT). Additionally, kinetic and kinematic data were recorded before and after treatment in the NoExo condition. Results The one-month training protocol was found to be a feasible strategy to train TFAs, as all participants smoothly completed the clinical protocol with no relevant mechanical failures of the APO. The walking performance of participants improved after the training. During the 6mWT in NoExo, participants in the Symmetry and Speed groups respectively walked 17.4% and 11.7% farther and increased walking speed by 13.7% and 17.9%, with improved temporal and spatial symmetry for the former group and decreased energetic expenditure for the latter. Gait analysis showed that ankle power, step width, and hip kinematics were modified towards healthy reference levels in both groups. In the Exo condition metabolic efficiency was reduced by 3% for the Symmetry group and more than 20% for the Speed group. Conclusions This study presents the first pilot study to apply a wearable robotic orthosis (APO) to assist TFAs in an overground gait rehabilitation program. The proposed APO-assisted training program was demonstrated as a feasible strategy to train TFAs in a rehabilitation setting. Subjects improved their walking abilities, although further studies are required to evaluate the effectiveness of the APO compared to other gait interventions. Future protocols will include a lighter version of the APO along with optimized assistive strategies.

Psychological assessment plays a large part in the practice of psychology. Over the years, steps have been taken towards ensuring ethical and culturally sensitive psychological assessment for underserved populations, but little is known about the current state of the field of assessment of deaf and hard-of-hearing (DHH) individuals. An exploratory survey of school and clinical psychologists who work with DHH clients (n = 30) was conducted to obtain a snapshot of the state of the field. The current article focuses on sociodemographic characteristics, clinical training, clinical experiences, and language abilities of clinical psychologists who work with DHH clients. Participants averaged 15 years of assessment experience and almost all participants had some type of specialized training in assessing DHH clients. More than half of participants reported their ability to use multiple languages and communication approaches as either excellent or good. Current findings were compared with a similar survey from nearly 50 years ago (Levine, E. S. (1974). Psychological tests and practices with the deaf: A survey of the state of the art. Volta Review, 76, 298–319), and significant differences were found in participants’ self-reported experience with DHH clients, training, and methods of communication.

Previous research has established a correlation between literacy skills and sign language skills among deaf children raised in signing families, but little research has examined the impact of early signing skills on the rate of growth of emergent literacy in early childhood. A subset of data was extracted from a larger dataset containing national longitudinal data from a three-year investigation of early literacy development of deaf children who were between the ages of three and six at the outset of the study. Selection criteria for inclusion in this limited sample included: 1) being rated as having little or no access to spoken language and 2) being raised in homes in which signs were regularly used as a means of communication (N = 56). Our purpose was twofold: 1) to examine and describe the trajectories of growth in letter and word identification skill for this sample in relation to the participants' initial ages; and 2) to assess the degree to which the presence or deaf parents in the home (DoD) and the receptive American Sign Language (ASL) skills of the participants impacted both the level of emerging print literacy and its rate of growth over the three year period. We hypothesized that both the presence of a deaf parent in the home and the acquisition of ASL skills, a strong native language, would contribute to both the overall letter and word identification skills and to the rates of growth of this skill over time. Results indicated that having a deaf parent did, indeed, impact emergent literacy attainment, but its effect was rendered nonsignificant when ASL skill was taken into consideration. Possession of stronger ASL skills, whether or not the children had deaf parents, contributed significantly to both the levels and rate of growth. The findings contribute to the body of work that emphasizes the importance early language skills (spoken or signed) to later academic success and dispels the myth that deaf children with deaf parents have exclusive access to the acquisition of these skills.

International audience; 1 Facio-Scapulo Humeral dystrophy (FSHD) is the third most common myopathy, affecting 1 amongst 10,000 individuals (FSHD1, OMIM #158900). This autosomal dominant pathology is associated in 95% of cases with genetic and epigenetic alterations in the subtelomeric region at the extremity of the long arm of chromosome 4 (q arm). A large proportion of the remaining 5% of cases carry a mutation in the SMCHD1 gene (FSHD2, OMIM #158901). Here, we explored the 3D organization of the 4q35 locus by three-dimensions DNA in situ fluorescent hybridization (3D-FISH) in primary fibroblasts isolated from patients and healthy donors. We found that D4Z4 contractions and/or SMCHD1 mutations impact the spatial organization of the 4q35 region and trigger changes in the expression of different genes. Changes in gene expression were corroborated in muscle biopsies suggesting that the modified chromatin landscape impelled a modulation in the level of expression of a number of genes across the 4q35 locus in FSHD. Using induced pluripotent stem cells (hIPSC), we further examined whether chromatin organization is inherited after reprogramming or acquired during differentiation and showed that folding of the 4q35 region is modified upon differentiation. These results together with previous findings highlight the role of the D4Z4 macrosatellite repeat in the topological organization of chromatin and further indicate that the D4Z4-dependent 3D structure induces transcriptional changes of 4q35 genes expression.

International audience; Fifteen years after the completion of first human genome sequencing, the technique is almost a commodity but there is still little evidence of its usefulness as a diagnostic, prognostic or therapeutic tool. In France, the France genomics plan 2025 was launched in 2015 with the goal of integrating genomic tests into clinical practice and developing a National genomics network including industrial partnerships. Reflection on scientific applications and operational or societal issues is needed to make recommendations to help better associate Genomics and the medicine of tomorrow. In the perspective of personalized Evidence-based Medicine, studies with an appropriate methodological level to improve the definition of evidence should be promoted. The many operational challenges require the implementation of organisations and means to streamline the process of results reporting, and regulatory adaptations concerning the status of professions involved, the management of data generated, and the consent of patients. In parallel, genetic training for healthcare professionals and raising awareness on genetic tests for the public should be considered. The ethical stake should also be taken into account, especially on the participation of the patient in decisions concerning them and integrating the notion of uncertainty into the information given. The sociological effects on the experience and expectations of patients and the general population towards genomic medicine should also be evaluated to improve information, prevention and support for people. Finally, medico-economic studies must be conducted to inform policy-makers on the cost-effectiveness of complete genome sequencing for population health.

CD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca

This study collected data on the use of ferric carboxymaltose (FCM) in a cancer patient population in France to evaluate the feasibility and the conditions of use of FCM in routine clinical practice beyond the limiting criteria of clinical trials. This observational, prospective study of patients with a solid tumour or a haematological malignancy who have received treatment with FCM after 01 July 2011 evaluated data about the circumstances of iron administration, concomitant medication and laboratory tests in the period from 3 months prior to the first FCM administration (baseline) until 3 months post-baseline. Data from 367 FCM-treated patients were analysed. FCM was mainly given as a single dose at baseline (69.2 %) and without additional erythropoiesis-stimulating agent (ESA, 64.3 %). The median total iron dose was 1000 mg per patient. Median haemoglobin (Hb) levels of FCM-treated patients improved from 10.3 g/dL (interquartile range 9.5, 11.1 g/dL) at baseline to 11.8 g/dL (11.1, 13.0 g/dL) until the end of the 3-month observational period. Patients treated with FCM alone or additional ESA achieved similar median Hb increase (1.3 [0.4, 2.1] g/dL and 1.4 [0.4, 2.5] g/dL, respectively). Patients with baseline Hb up to 11.0 g/dL and serum ferritin up to 500 ng/mL and beyond achieved stable median Hb levels ≥11.0 g/dL without signs of iron overload. No severe or serious adverse reaction and no hypersensitivity reactions were reported. The results of this observational study confirm the effectiveness and tolerability of FCM when given in clinical routine practice alone or in combination with an ESA.

Participation is key to the success of cancer screening. Identifying the reasons for nonparticipation is therefore essential. The present analysis of the EDIFICE (etude sur le depistage des cancers et ses facteurs de compliance [survey on cancer screening and compliance factors]) surveys (n = 1463) found 36.4% of current smokers and 26.3% of former smokers intended to participate in a lung cancer screening program. Discrepancies exist between the screening program target populations and the individuals who actually intend to undergo screening. Background: Lung cancer (LC) screening (LCS) with annual low-dose computed tomography scans has been seen to reduce the specific and overall mortality in selected populations. However, participation is key to successful screening programs. The EDIFICE (etude sur le depistage des cancers et ses facteurs de compliance [survey on cancer screening and compliance factors]) nationwide observational surveys are used to assess behavior related to cancer screening programs in France. Materials and Methods: Using comprehensive multivariate stepwise logistic regression analyses of data from current and former cigarette smokers, we sought to identify the explanatory factors associated with the intention to participate in an LCS program. Results: Of the 1463 respondents with no personal history of cancer, 263 (36.4%) of the current cigarette smokers and 170 (26.3%) of the former cigarette smokers stated their willingness to participate in an LCS program. The explanatory factors differed between current cigarette smokers (already screened for LC: odds ratio PRI, 2.81; < 30 pack-years: OR, 2.69; intention to quit smoking: OR, 1.96; no social vulnerability: OR, 2.15) and former cigarette smokers (comorbidities: OR, 0.31). The usual eligibility criteria were not significantly explanatory. Conclusion: Our findings highlight the discrepancy that exists between target populations and individuals who actually intend to participate in a screening program for LC, with subsequent potential effects on the participation rates and, thus, on the efficacy of screening. (C) 2018 Elsevier Inc. All rights reserved.

Objectives The incidence of skin cancers, melanoma in particular, is increasing rapidly. Consequently, specific recommendations for sun-protection measures now exist. This survey set out to assess the compliance of the general population with these guidelines. Methods The French nationwide observational survey, EDIFICE Melanoma, was conducted (28 September to 20 October 2011) through phone interviews of a representative sample of 1502 subjects aged ≥ 18 years, using the quota method. Sun-protection was defined as frequent or systematic use of clothes or sunscreen. The group of individuals who declared exposure to the sun (N = 1172) was subdivided: risk-takers (N = 442), and those who used sun protection (N = 730). Results Risk-takers were significantly more often male (62% vs. 44%, P

The aim of this study was to investigate whether the labor market mobility of a population of cancer survivors 2 years after diagnosis differed compared to the French general population by focusing on the differences between self-employed workers and salaried staff. Coarsened exact matching was implemented to reduce the sampling bias introduced by the comparison of individuals from two different surveys. Then, labor market mobility was analyzed by estimating transition probability matrices from 2010 to 2012 under the framework of a continuous-time Markov technique and by estimating a two-step model. Salaried employees and self-employed workers from the general population were more likely to remain employed 2 years after 2010 compared to salaried employees and self-employed workers who survived cancer. There was no major difference between salaried and self-employed workers surviving cancer in terms of job retention. French workers surviving cancer face the same difficulties that were observed in the National Cancer Survey of 2004: unemployment and inactivity caused by the diagnosis of cancer. Among cancer survivors, self-employed workers do not seem to be particularly more affected by inactivity than salaried staff. However, unemployment insurance is not compulsory for them, contrary to salaried staff. In this regard, self-employed workers might be a more vulnerable group.

International audience; CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase C gamma 1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment.

International audience; Human telomeres are protected from DNA damage by a nucleoprotein complex that includes the repeat-binding factor TRF2. Here, we report that TRF2 regulates the 5' exonuclease activity of its binding partner, Apollo, a member of the metallo-beta-lactamase family that is required for telomere integrity during S phase. TRF2 and Apollo also suppress damage to engineered interstitial telomere repeat tracts that were inserted far away from chromosome ends. Genetic data indicate that DNA topoisomerase 2alpha acts in the same pathway of telomere protection as TRF2 and Apollo. Moreover, TRF2, which binds preferentially to positively supercoiled DNA substrates, together with Apollo, negatively regulates the amount of TOP1, TOP2alpha, and TOP2beta at telomeres. Our data are consistent with a model in which TRF2 and Apollo relieve topological stress during telomere replication. Our work also suggests that cellular senescence may be caused by topological problems that occur during the replication of the inner portion of telomeres.

Background In stage III colorectal cancer (CRC), adjuvant chemotherapy (CT) is usually prescribed within two months after curative surgery. Whether or not delaying initiation of CT affects survival is still debated. Material and methods We performed a meta-analysis (MA) of all published studies (full papers or abstracts) comparing delayed CT with standard care. Studies were obtained from a PubMed query (keywords: CRC, adjuvant treatment, delay of CT), a review (Chau et al., 2006), cross-checking references and abstracts from the proceedings of ASCO, ASCO GI and WCGI annual meetings. We chose a cutoff delay of 8 weeks. Risk Ratios (RRs) were calculated from the recorded events (deaths, relapses). We used EasyMA software (fixed-effect model). Results Fourteen studies (including four abstracts) were identified (17,645 patients; 5952 males, 5151 females, mean age 70 years). Of these, three could not be statistically analysed and three used another cutoff (4, 5 or 6 weeks), leaving 8 studies for main MA (13,158 patients; 3932 males, 3644 females, 5942 missing data; 5576 colon cancers, 6677 rectal, 1265 missing data). Delaying CT more than 8 weeks was associated to worse Overall Survival (OS) (RR: 1.20; 95% Confidence Interval (CI) 1.15–1.26). In the MA including all studies whatever their cutoff, longer delay was similarly associated to a worse OS but not a worse Relapse-Free Survival (RFS) (five studies). Conclusion Adjuvant chemotherapy should be started within 8 weeks after surgery. Delaying the initiation of adjuvant CT for more than 8 weeks after surgery significantly decreased OS but not RFS. This discrepancy might be due to factors not directly related to cancer (post-operative complications, social status) or to a more accurate appraisal of death.

Background The Renal Insufficiency and Anticancer Medications (IRMA) study reported a renal insufficiency (RI) prevalence of 50%–60% in a population of almost 5000 patients with solid tumors, 80% of whom were being treated with anticancer drugs that either necessitated dosage adjustment or were potentially nephrotoxic drugs. A national multicenter study from 15 cancer centers in France analyzed IRMA data on patients with prostate cancer. Patients and Methods Data on patients with prostate cancer from the IRMA study were analyzed. Renal function was calculated using Cockcroft-Gault and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas to estimate the prevalence of RI. Anticancer drugs' potential renal toxicity and need for dosage adjustment were detailed. Results Of the 222 IRMA patients with prostate cancer, 14.9% had a serum creatinine (SCr) level of > 110 μmol/L. When using Cockcroft-Gault and aMDRD formulas, 62.6% and 55.9%, respectively, of the patients had RI. Of the 228 anticancer drug prescriptions, 82.9% required dose adjustments for RI or were drugs with no available data on their administration in patients with RI. Of the patients treated, 86.9% received ≤ 1 such drug, but only 29.1% received nephrotoxic drugs. Conclusion The prevalence of RI in patients with prostate cancer was very high in spite of a normal SCr level in most cases. Some anticancer drugs, particularly some bisphosphonates and platinum salts, might be nephrotoxic and/or need dosage adjustment. However, other important drugs in prostate cancer, such as docetaxel, neither require dose reduction nor present with potential nephrotoxicity. Both issues were significantly more important in the patients with bone metastases compared with those with nonmetastatic disease.

Purpose Intergroupe Francophone de Cancerologie Thoracique-0401 phase II trial aimed to evaluate the efficacy and safety of gefitinib as a first-line treatment for patients with adenocarcinoma with bronchioloalveolar carcinoma subtype (ADC-BAC). Methods Chemotherapy-naive patients ( n = 88) with advanced ADC-BAC were treated with 250 mg/d of gefitinib. The primary objective was assessment of disease control rate (DCR [objective response + stable disease]) at 3 months using World Health Organization criteria. A disease control rate of 25% or greater would be of interest in this patient population. Progression-free survival (PFS), overall survival (OS), and toxicity were the secondary criteria. Clinical and disease characteristics that conferred a favorable prognosis under gefitinib were also analyzed. Results Disease control was achieved in 25 patients (29.4%); 11 patients (12.9%) had partial response and 14 (16.4%) had stable disease. Median PFS was 2.9 months (95% confidence interval [CI], 2.3–3.2) and median OS was 13.2 months (95% CI, 10.2–17.3). Never smokers, patients with low respiratory symptoms score, occurrence of cutaneous rash, and nonmucinous ADC-BAC subtype were associated with increased probability of disease control. Nonmucinous ADC-BAC was associated with increased PFS and OS at 3 years. Patients with nonmucinous BAC had longer OS and PFS compared with patients with other ADC-BAC variants; median PFS for nonmucinous BAC was 11.3 months (95% CI, 3.2–14.7), whereas it was 2.6 months (95% CI, 2.1–3) for mucinous BAC. As expected, toxicity was low, with dermatological problems, diarrhea, and nausea being the most common adverse events. Conclusion Results from the Intergroupe Francophone de Cancerologie Thoracique-0401 trial demonstrate that gefitinib combines efficacy with low toxicity and is, therefore, suitable as a first-line treatment of advanced ADC-BAC, particularly in patients with nonmucinous BAC subtype.

The Renal Insufficiency and Anticancer Medications (IRMA) study is a French national, observational study which demonstrated the high prevalence of abnormal renal function in a population of 4684 solid tumor patients. Among them, 50-60% had decreased renal function, and 80% were treated with anticancer drugs that either necessitated dosage adjustment in case of renal insufficiency (RI) or were potentially nephrotoxic drugs. Since elderly patients are well-known to have reduced renal function, either due to physiological aging or their disease/medication history, a subgroup analysis of this particular population of patients was performed. In 1553 IRMA patients whose age was > or =65 years, the prevalence of RI was very high in spite of normal serum creatinine values in most cases. Anticancer drugs used may be nephrotoxic or need dosage adjustment in a high number of cases.

Aims: The Epidermal Growth Factor-Receptor (EGF-R) is frequently overexpressed in colorectal carcinoma (CRC) and patients can benefit from anti-EGF-R therapy. Yet, the relationship, within tumours, between EGF-R and the activity of downstream effectors such as the non-receptor tyrosine kinase p60c-src and the signal transducer and activator of transcription 3 (STAT3) has not been extensively analyzed. Methods and results: We evaluated EGF-R, tyrosine 416-phosphorylated p60c-src (P-p60c-src), STAT3 and tyrosine 705- phosphorylated STAT3 (P-STAT3) on Tissue Micro Array (TMA) from 126 patients with CRC. Composite immunohistochemistry scores based on the intensity of labelling and the percentage of positive cells were determined on TMA for EGF-R, P-p60c-src, STAT3 and P- STAT3. A high score was found in 56%, 61%, 62% and 27% of the cases for EGF-R, P-p60c-src, STAT3 and P-STAT3 respectively. There was a significant correlation between EGF-R and P-p60c-src (p =0 .006) and between P-p60c-src and P-STAT3 (p =0 .0009). STAT3 was significantly correlated with vascular emboli ( p =0 .03) and perineural invasion (p =0 .02). Conclusions: The correlations between EGF-R, P-p60-src and P-STAT3 and some stage-related pathological features point to a critical role for a EGF-R-connected p60c-src-kinase-mediated pathway involving STAT3 and contributing to cell survival and proliferation within CRC tumours.

Nowadays, nanomedicine brings new opportunities for diagnosis and treatment through innovative combinations of materials structured at the nanoscale, biomolecules and physicochemical processes. If the intrinsic properties of nanomaterials appear of major importance in this new discipline, the functionalization of these nanotools with biomolecules improves both their biocompatibility and efficacy. This is the case of carbohydrate derivatives, natural or synthetic, which are increasingly being used in nanostructures for medical purposes. As in current medicine, sugars are used to mimic their physiological roles. Indeed, carbohydrates enhance the solubility and reduce the clearance of drugs. They are used to mask immunogenic components of nano-objects and escape the body defenses and finally facilitate the delivery to the target tissue. All these properties explain the growing importance of sugars in nanomedicine.

Introduction Today, a growing need exists for greater research into cancer survivorship, focusing on different spheres of the day-to-day life of diagnosed patients. This article describes the design and implementation of VICAN (VIe apres le CANcer), a national survey on French cancer survivors. Method and analysis The target population included patients aged 18–82, diagnosed with cancer between January and June 2010, and registered in one of the three main French Health Insurance Schemes. It was restricted to 12 tumour sites. Sampling was stratified using a non-proportional allocation, based on age at diagnosis (18–52 and 53–82) and tumour site. Data were collected from telephone interviews with patients 2 and 5 years after diagnosis, a medical survey completed by the physician who initiated cancer treatment, and information from the national medicoadministrative database on reimbursement data and hospital discharge records. First data collection, 2 years after diagnosis, occurred between March and December 2012. Second data collection, 5 years after diagnosis, will be conducted in 2015. Analyses will be conducted on various outcomes: quality of life, health status and psychosocial conditions, with a particular focus on the impact of cancer diagnosis on the labour market. The variety of measurements included in the survey will enable us to control a wide range of factors. Ethics and dissemination The methodology of the VICAN survey was approved by three national ethics commissions. Results of the study will be disseminated through national and international research conferences, and in articles published in international peer-reviewed journals.

We performed a meta-analysis of all published studies relating intratumoural microvessel density (MVD) (45 studies) or vascular endothelial growth factor (VEGF) expression (27 studies), both reflecting angiogenesis, to relapse free (RFS) and overall survival (OS) in colorectal cancer (CRC). For each study, MVD impact was measured by risk ratio between the two survival distributions with median MVD as cutoff. Eleven studies did not mention survival data or fit inclusion criteria, six were multiple publications of same series, leaving 32 independent studies for MVD (3496 patients) and 18 for VEGF (2050 patients). Microvessel density was assessed by immunohistochemistry, using antibodies against factor VIII (16 studies), CD31 (10 studies) or CD34 (seven studies). Vascular endothelial growth factor expression was mostly assessed by immunohistochemistry. Statistics were performed for MVD in 22 studies (the others lacking survival statistics) including nine studies (n = 957) for RFS and 18 for OS (n = 2383) and for VEGF in 17 studies, including nine studies for RFS (n = 1064) and 10 for OS (n = 1301). High MVD significantly predicted poor RFS (RR = 2.32 95% CI: 1.39-3.90; P0.001) and OS (RR = 1.44; 95% CI: 1.08-1.92; P = 0.01). Using CD31 or CD34, MVD was inversely related to survival, whereas it was not using factor VIII. Vascular endothelial growth factor expression significantly predicted poor RFS (RR = 2.84; 95% CI: 1.95-4.16) and OS (RR=1.65; 95% CI: 1.27-2.14). To strengthen our findings, future prospective studies should explore the relation between MVD or VEGF expression and survival or response to therapy (e.g. antiangiogenic therapy). Assessment of these angiogenic markers should be better standardised in future studies.

International audience; Objective: We investigated the link between DNA hypomethylation and clinical penetrance in facioscapulohumeral dystrophy (FSHD) because hypomethylation is moderate and heterogeneous in patients and could not thus far be correlated with disease presence or severity. Methods: To investigate the link between clinical signs of FSHD and DNA methylation, we explored 95 cases (37 FSHD1, 29 asymptomatic individuals carrying a shortened D4Z4 array, 9 patients with FSHD2, and 20 controls) by implementing 2 approaches: methylated DNA immunoprecipitation and sodium bisulfite sequencing. Results: Both methods revealed statistically significant differences between asymptomatic carriers or controls and individuals with clinical FSHD, especially in the proximal region of the repeat. Absence of clinical expression in asymptomatic carriers is associated with a level of methylation similar to controls. Conclusions: We provide a proof of concept that the targeted approaches that we describe could be applied systematically to patient samples in routine diagnosis and suggest that local hypomethylation within D4Z4 might serve as a modifier for clinical expression of FSHD phenotype. Classification of evidence: This study provides Class III evidence that assays for hypomethylation within the D4Z4 region accurately distinguish patients with FSHD from individuals with D4Z4 contraction without FSHD.

Epidemiological and experimental studies indicate that early vascular dysfunction occurs in low-birth-weight subjects, especially preterm (PT) infants. We recently reported impaired angiogenic activity of endothelial colony-forming cells (ECFCs) in this condition. We hypothesized that ECFC dysfunction in PT might result from premature senescence and investigated the underlying mechanisms. Compared with ECFCs from term neonates (n = 18), ECFCs isolated from PT (n = 29) display an accelerated senescence sustained by growth arrest and increased senescence-associated β-galactosidase activity. Increased p16(INK4a) expression, in the absence of telomere shortening, indicates that premature PT-ECFC aging results from stress-induced senescence. SIRT1 level, a nicotinamide adenine dinucleotide-dependent deacetylase with anti-aging activities, is dramatically decreased in PT-ECFCs and correlated with gestational age. SIRT1 deficiency is subsequent to epigenetic silencing of its promoter. Transient SIRT1 overexpression or chemical induction by resveratrol treatment reverses senescence phenotype, and rescues in vitro PT-ECFC angiogenic defect in a SIRT1-dependent manner. SIRT1 overexpression also restores PT-ECFC capacity for neovessel formation in vivo. We thus demonstrate that decreased expression of SIRT1 drives accelerated senescence of PT-ECFCs, and acts as a critical determinant of the PT-ECFC angiogenic defect. These findings lay new grounds for understanding the increased cardiovascular risk in individuals born prematurely and open perspectives for therapeutic strategy.

International audience; Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is thought to underlie FSHD pathophysiology. However, no one knows what triggers muscle defect and when alteration arises. To gain further insights into the molecular mechanisms of the disease, we evaluated at the molecular level, the perturbation linked to the FSHD genotype with no a priori on disease onset, severity or penetrance and prior to any infiltration by fibrotic or adipose tissue in biopsies from fetuses carrying a short pathogenic D4Z4 array (n 5 6) compared with fetuses with a non-pathogenic D4Z4 array (n 5 21). By measuring expression of several muscle-specific markers and 4q35 genes including the DUX4 retrogene by an RT-PCR and western blotting, we observed a global dysregulation of genes involved in myogenesis including MYOD1 in samples with

International audience; : Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first molecular dysregulations occur is still unknown. Our aim was to determine whether molecular dysregulations can be identified during FSHD fetal muscle development. We compared muscle biopsies derived from FSHD1 fetuses and the cells derived from some of these biopsies with biopsies and cells derived from control fetuses. We mainly focus on DUX4 isoform expression because the expression of DUX4 has been confirmed in both FSHD cells and biopsies by several laboratories. We measured DUX4 isoform expression by using qRT-PCR in fetal FSHD1 myotubes treated or not with an shRNA directed against DUX4 mRNA. We also analyzed DUX4 downstream target gene expression in myotubes and fetal or adult FSHD1 and control quadriceps biopsies. We show that both DUX4-FL isoforms are already expressed in FSHD1 myotubes. Interestingly, DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes, which is confirmed by the level of expression of DUX4 downstream genes. We observed that TRIM43 and MBD3L2 are already overexpressed in FSHD1 fetal quadriceps biopsies, at similar levels to those observed in adult FSHD1 quadriceps biopsies. These results indicate that molecular markers of the disease are already expressed during fetal life, thus opening a new field of investigation for mechanisms leading to FSHD.

International audience; In this mini-review, we focus on different strategies to bring nanotools specifically to cancer cells. We discuss about a better targeting of tumor, combining the characteristics of tumor environment, the increase in nanoparticles life time, the biomarkers overexpressed on cancer cells and different physical methods for non invasive therapies. Here we detail the necessity of a synergy between passive and active targeting for an actual specificity of cancer cells.

Although oncologists seem unable to name the new paradigm of cancer treatment, a certain trend seems to take shape in favor of the precision medicine. To paraphrase Mickael P. Link, President of the American Society of Clinical Oncology, precision medicine identifies and makes the most of the weaknesses of cancer genetics so that the tumoral growth can be stopped. Doubtless, major advances in this oncologic medicine of precision have been observed throughout 2012. These advances have first of all affected the theranostics. This is how two new oncogenic drivers were discovered in lung adenocarcinoma. The first one ROS1 is situated in 6q. 22 chromosome. ROS1 is observed in 1 % of the cases and would seem to be sensitive to the anaplastic lymphoma kinase (ALK) and C-MET inhibitors [1]. Kinase inhibitor fusion 5B—rearranged during transfection [1], the second, is observed in 1.3 % of non-small cell lung cancer (NSCLC). Two aspects of these discoveries are important to underline because there are agents targeting these molecular modifications (crizotinib and a tyrosine kinase inhibitor anti-RET) and also because these molecular targets exist in other tumoral types: glioblastoma or cholangiocarcinoma for ROS1. In addition to this progress in theranostics, numerous advances have concerned new, soon-to-be-available agents in oncology practice. This is the way crizonitinb, a powerful inhibitor of ALK tyrosine kinase receptor [2], demonstrates its efficacy in the ALK-positive NSCLC previously treated with first-line platinum-based chemotherapy. This treatment is superior to standard second-line chemotherapy with a striking hazard ratio (HR) of 0.49 [3]. Regorafenib [4] offers a new therapeutic option in metastatic colorectal cancers in second-line treatment and in GIST. Cabozantinib, a new potent inhibitor of VEGFR and MET and VEGFr2 [5], shows promise in several tumor types, such as prostate, breast, and hepatocarcinoma. Dabrafenib, a new anti-RAF agent can achieve an HR of 0.35 for progression-free survival in patients with metastatic melanoma [6]. MEK blockade is one of the last novelties in signaling. Take the example of trametinib, which compares favorably to chemotherapy in metastatic melanoma (HR0 0.54 (0.32–0.92)) [7]. Signaling pathways are not the only process that is “targetable.” Immunotherapeutics is currently regaining its former glory. The stimulation of the immune system against tumors through targeting regulatory T cells is taking shape. It is now evident that monoclonal antibodies directed against cytotoxic T lymphocyte antigen 4 or programmed cell death 1 represent dramatic progress in the management of melanoma [8]. Thanks to new agents, there is even more hope for our patients

The Mini-Mental State Exam (MMSE) is commonly used to screen cognitive function in a clinical setting. The measure has been published in over 50 languages; however, the validity and reliability of the MMSE has yet to be assessed with the culturally Deaf elderly population. Participants consisted of 117 Deaf senior citizens, aged 55-89 (M = 69.44, SD = 8.55). Demographic information, including state of residence, age, and history of depression, head injury, and dementia diagnoses, were collected. A standard form of the MMSE was used with modification of test administration and stimuli including translation of English test items into a sign-based form and alteration of two items in order to make them culturally and linguistically appropriate. Significant correlations were observed between overall test score and education level (r = .23, p = .01) as well as test score and age (r = -.33, p < .001). Patterns of responses were analyzed and revealed several items that were problematic and yielded a fewer correct responses. These results indicate that clinicians need to be aware of cultural and linguistic factors associated with the deaf population that may impact test performance and clinical interpretation of test results. On the basis of these data, there is an increased risk of false positives obtained when using this measure. Further research is needed to validate the use of this measure with the culturally Deaf population.

Microsatellite Instability (MSI) status is a good prognostic factor for colorectal cancer (CRC) but its predictive value for chemosensitivity remains controversial. A previous meta-analysis (MA) in the adjuvant setting showed that MSI-high (H) status did not predict the efficacy of chemotherapy. The predictive value of MSI status on the effect of metastatic chemotherapy was investigated by MA.Studies were identified by electronic search through PubMed, Embase and ASCO proceedings online databases, using several key words (colorectal cancer, chemotherapy, microsatellite instability). For each study, the ratio of response rate (RR), complete (CR) and partial response (PR) divided by stable disease and progression was calculated. From 190 articles and 100 abstracts, only eight independent studies were selected. The data were analysed with a random-effect model (due to heterogeneity between studies) using EasyMA software. Statistical calculations were performed on six studies representing 964 patients (mean age 63 years; 91 MSI-H; 873 microsatellite stable (MSS) tumours). A total of 287 patients received 5-fluorouracil (5FU)-based chemotherapy, whereas 678 patients received combinations of 5FU or capecitabine with oxaliplatin and/or irinotecan.No benefit of metastatic chemotherapy in terms of RR for MSI-H patients compared with MSS patients was found. The global hazard ratio (HR) for RR was 0.82 (95% confidence interval, CI: 0.95; 0.65-1.03; p=0.09).MSI status does not predict the effect of chemotherapy which is similar in MSI-H and MSS metastatic CRC tumours.

International audience; The localization of genes within the nuclear space is of paramount importance for proper genome functions. However, very little is known on the cis-acting elements determining subnuclear positioning of chromosome segments. We show here that the D4Z4 human subtelomeric repeat localizes a telomere at the nuclear periphery. This perinuclear activity lies within an 80 bp sequence included within a region known to interact with CTCF and A-type Lamins. We further show that a reduced level of either CTCF or A-type Lamins suppresses the perinuclear activities of D4Z4 and that an array of multimerized D4Z4 sequence, which has lost its ability to bind CTCF and A-type Lamins, is not localized at the periphery. Overall, these findings reveal the existence of an 80 bp D4Z4 sequence that is sufficient to position an adjacent telomere to the nuclear periphery in a CTCF and A-type lamins-dependent manner. Strikingly, this sequence includes a 30 bp GA-rich motif, which binds CTCF and is present at several locations in the human genome.

Dermatological effects are among the most frequent side-effects in patients receiving erlotinib (Tarceva). However, there no official recommendations on the preventive or curative management of those erlotinib-related skin effects (ERSE). The "Prise En Charge des Effets Dermatologiques sous Erlotinib" (PRECEDE) study was designed to study how ERSE are being managed in France.The PRECEDE study is an observational retrospective study which included every nonsmall cell lung cancer patients treated with erlotinib in seven cancer centers in France from January 2005 to December 2007. Data related to preventive or curative treatment of ERSE were collected from the medical files of the patients.Two hundred and thirty-four patients were included; 48.7% of them had been delivered information on the potential occurrence of ERSE and 15.8% of those 234 patients had had prescription of drugs to be taken in case of ERSE, while 65.0% presented with ERSE which resolved in the majority of cases (86.2% of the patients), either spontaneously or under treatment. In the 85 patients in whom treatment was successful, 178 drug prescriptions comprising 35 different drugs were recorded.ERSE are frequent but regress in most cases, spontaneously or under treatment. However, there is still a wide variety of drugs used. This demonstrates that there is a need for recommendations on the management of ERSE in order to prevent and treat this erlotinib-related effect.

International audience; The Renal Insufficiency and Anticancer Medications (IRMA) study is a French national, observational study which demonstrated the high prevalence of abnormal renal function in a population of 4,684 solid tumour patients. Among them, 50–60% had decreased renal function defined as CrCl below 90 and 80% were treated with anticancer drugs that either necessitated dosage adjustment in case of RI or were potentially nephrotoxic drugs. Since patients and drugs used differ depending on the type of tumour, the IRMA Study Group started analyses in different subgroups of patients. In the 1898 IRMA patients with breast cancer, the prevalence of RI was still very high in spite of a normal serum creatinine in almost all cases. Some anticancer drugs, as in particular some bisphosphonates, capecitabine and platinum salts, may be nephrotoxic and/or need dosage adjustment. However other important drugs in breast cancer do not require dose reduction, and do not present with potential nephrotoxicity (anthracyclines, taxanes, trastuzumab). Both issues seem to be slightly but significantly more important in patients with bone metastases as compared to patients with a non-metastatic disease.

The Renal Insufficiency and Anticancer Medications (IRMA) study reported the high prevalence of renal insufficiency in cancer patients. In this special report, we focused on patients with lung cancer, emphasizing some specific findings in this population of patients. Data on patients with lung cancer who were in the IRMA study were analyzed. Renal function was calculated using Cockcroft-Gault and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas to estimate the prevalence of renal insufficiency (RI) according to the KDOQI-KDIGO definition. Anticancer drugs were studied with regard to their potential renal toxicity and need for dosage adjustment. Of the 445 IRMA lung cancer patients, 14.4% had a serum creatinine (SCR) levelor =110 micromol/L. However, when they were assessed using the formulas, 62.1 and 55.9% had abnormal renal function. Of the 644 anticancer drug prescriptions, 67.5% required dose adjustments for RI or were drugs with no available data, and 78.3% of the patients received at least one such drug. Furthermore, 71.6% received potentially nephrotoxic drugs. Seventy percent of the patients had anemia but prevalence was not significantly associated with the existence of associated renal insufficiency. In the 445 IRMA patients with lung cancer, the prevalence of RI was high in spite of a normal SCR in most cases. Some anticancer drugs such as platinum salts may be nephrotoxic and need dosage adjustment. However, other important drugs such as gemcitabine do not require dose reduction and do not present with a high potential for nephrotoxicity. Lung cancer patients often present with anemia, which was not associated with the presence of RI.

International audience; BACKGROUND: The EDIFICE survey aimed to investigate the compliance of the general population to the screening tests available in France for the 4 most common cancers: breast, colorectal, prostate and lung. Implementation of breast cancer screening has been generalized in France since 2003: women aged between 50 and 74 years are systematically invited to perform a mammography every second year. Results pertaining to breast cancer are reported hereafter. METHODS: This nationwide observational survey was carried out in France from 18 January to 2 February 2005 among representative samples of 773 women aged between 40 and 75 years and 600 general practitioners (GPs). Information collected included socio-demographic characteristics, attitude towards cancer screening and actual experience of cancer screening, as well as GPs' practice regarding screening. The precision of the results is +/- 4.3% for a 95% confidence interval. RESULTS: Among the 507 participating women aged between 50 and 74 years, 92.5% (469/507) had undergone at least one mammography: 54.6% (256/469) underwent this test on their own initiative and 44.6% (209/469) of women performed it in the framework of a systematic screening plan. Most women participating in the systematic screening (89.0% i.e. 186/209) had a mammography within the last dating from less than 2 years versus 73.8% (189/256) of those who performed it outside the screening program (Chi(2) test; p

Cerebral lateralization for speech in right-handed normal hearing and deaf adolescents was assessed using the dual-task paradigm. Subjects with normal hearing and deafness acquired after 3 years of age displayed left hemispheric dominance for speech production, whereas both congenitally deaf and those with an early acquired deafness (onset 6–36 months) showed atypical, anomalous cerebral representation. These results suggest the presence of a developmental critical period for cerebral lateralization during which exposure to adequate environmental stimulation may be needed to activate left hemispheric dominance for speech.

To assess the efficacy of oral physostigmine for the treatment of Alzheimer's disease, 20 patients were entered into a clinical trial. All patients underwent a dose-finding phase (two weeks), followed by an open trial (two weeks), and a double-blind crossover phase (two weeks drug, two weeks placebo). Extensive neuropsychological testing (Buschke Selective Reminding procedure, category generation, picture recognition, finger tapping) and measurement of systemic cholinergic parameters were measured during each of these phases. Patients were classified as physostigmine responders and nonresponders based on a priori established criteria. Using these, nine patients were found to respond to physostigmine, while 11 were classified as nonresponders. During baseline conditions, responders when compared to nonresponders were found to have higher concentrations of red blood cell (RBC) choline (Ch) and higher ratios of RBC Ch to plasma Ch. Neuropsychological tests were found to fall into one of three categories. The first group of tests were sensitive to drug effects and differentiated physostigmine responders from nonresponders; the second group was found to predict responsiveness; and the third group was neither predictive nor sensitive to drug effects.

Microsatelite instability (MSI) is the consequence of the inactivation of a mismatch repair gene and is observed in approximately 15% of colon cancer cases. Patients with MSI colon cancer do not benefit from 5-fluorouracil (5-FU)-based chemotherapy. A current treatment of reference for colon cancer is a combination of 5-FU and oxaliplatin (FOLFOX). The aim of this study was to determine the efficiency of the FOLFOX treatment in patients with metastatic MSI colon cancer.Tumour specimens were collected from patients with metastatic colon cancer treated with FOLFOX 4 modified or FOLFOX 6; these two regimens are based on 85 mg/m2 and 100 mg/m2 oxaliplatin, respectively. The MSI status was assessed by measuring the length of five monomorphic mononucleotide markers. The FOLFOX regimen was evaluated as a first-line treatment according to WHO criteria.Forty patients (22 men, 18 women), median age 63.5 years (27-83 years) were treated with FOLFOX 4 or 6. Nine patients had tumours exhibiting high MSI (MSI group) and 31 patients had tumours exhibiting microsatellite stability (MSS group). In the MSS group, 11 partial responses (36%) were observed, while there were only two in the MSI group (22%) (no significant difference). The two patients who were responders in the MSI group were treated with FOLFOX 6. The overall survival was not significantly different for MSI and MSS patients.No significant differences in the overall response rate or overall survival between the two groups of patients were observed. However, these results suggest that patients with MSI colon cancer are more sensitive to a higher dose of FOLFOX.

Syndrome of inappropriate antidiuretic hormone secretion is frequent in small-cell lung carcinomas. We report on a case of syndrome of inappropriate antidiuretic hormone secretion after each of the first 2 cycles of chemotherapy for small-cell lung cancer. The association with chemotherapy-induced tumor lysis is proposed, particularly based on the course of antidiuretic hormone levels, and a review of the literature is presented. Syndrome of inappropriate antidiuretic hormone secretion can occur during tumor lysis syndrome.

Conducting assessment with individuals with physical disability, visual impairment or blindness, and hearing impairment or deafness poses significant challenges for the neuropsychologist. Although standards for psychological testing have been devised to address assessment of persons with disabilities, little research has been conducted to validate neuropsychological test accommodation and modification practices that deviate from standard test administration or to develop test parameters and interpretive guidelines specifically for persons with different physical or sensory disabilities. This paper reviews issues pertaining to neuropsychological test selection and administration, common accommodation and modification practices, test development and validation, and disability-related factors that influence interpretation of test results. Systematic research is needed to develop methodological parameters for testing and to ensure reliable and valid neuropsychological assessment practices for individuals with physical or sensory disabilities.

Carcinomatous meningitis is a major complication in Non Small Cell Lung Cancer (NSCLC). Despite treatment with radiotherapy alone or in combination with intrathecal and systemic chemotherapy, its prognosis remains poor.We report a case of a female non-smoker with adenocarcinoma with bronchoalveolar features presenting with carcinomatous meningitis three years after the diagnosis of her primary tumour. Gefitinib treatment was proposed because of the persistence of meningitic symptoms despite cranial irradiation. Clinical response was observed within 3 weeks and lasted for 9 months.Gefitinib may be effective in treating carcinomatous meningitis complicating NSCLC and should be considered in this situation given the absence of effective alternatives.

Objective: To evaluate the clinical impact of using a silver-releasing hydroalginate dressing to minimise the risk of local infection in colonised chronic wounds. Method: This was a randomised (stratification according to wound type) open-label multicentre comparative two-arm parallel-group study. Thirteen centres recruited 99 patients with either a venous leg ulcer or a pressure ulcer. None of the wounds required systemic antibiotics or were associated with lymphangitis and/or fever, but at least two of the following criteria had to be present: continuous pain; erythema; oedema; heat; and moderate to high levels of serous exudate. Patients were allocated to receive either a silver-releasing hydroalginate dressing (Silvercel, the test group) or a pure calcium alginate dressing (Algosteril, the control group). Wounds were assessed daily over 14 days to complete a modified ASEPSIS index to evaluate risk of infection, and then weekly for two additional weeks. A global wound severity score and area tracings were recorded weekly. Results: Fifty-one and 48 patients were randomised in the test and control groups respectively: 28 pressure ulcers and 71 venous leg ulcers. The total mASEPSIS score over 14 days did not differ significantly between groups: 95.4 ± 62.2 and 104.2 ± 72.8 in control and test groups respectively (p=0.791). Of the patients who completed the total four-week study duration, four out of 38 (10.5%) in the control group and none of the 40 in the test group were treated with systemic antibiotics at the final visit (p=0.053). According to the investigators, fewer wounds developed a clinical infection over the four-week follow-up in the test group (33% versus 46%; p=0.223). Overall, the four-week closure rate was statistically greater in the test group (0.32 ± 0.57cm2/day versus 0.16 ± 0.40cm2/day; p=0.024). Compared with baseline, the absolute decrease in wound severity score at week four was higher in the test group (−5.6 ± 3.2 versus −4.1 ± 4.3; p=0.063); this was also true of the percentage reduction (−32 ± 17% versus −23 ± 25%; p=0.034). Poor dressing acceptability and/or tolerability was noted in five out of 48 patients (10.4%) in the control group and in five out of 51 (9.8%) in the test group. Conclusion: This study suggests that the use of silver-releasing dressings in the management of wounds at high risk of infection may have a clinically favourable influence on wound prognosis; the dressings also appeared to be well tolerated. However, the evaluation of these advantages in controlled clinical trials is complex and requires potent studies and the development of more specific endpoints than those currently used. Declaration of interest: This study was funded by a grant from Johnson and Johnson Wound Management.

The use of epidermal growth factor receptor (EGFR) inhibitors for the treatment of solid tumours is increasing. However, the tolerability profile for EGFR-inhibitors, such as the monoclonal antibody cetuximab and the tyrosine kinase inhibitor erlotinib, is characterised by a unique group of skin reactions dominated by an acneiform eruption, xerosis, eczema and changes in the hair and nails. The possibility that this skin toxicity correlates with anti-tumour activity offers the potential to titrate dosing on a case-by-case basis. These skin effects may constitute a significant obstacle to treatment compliance. Accordingly, there is a need for consistent, multi-disciplinary management strategies that will allow patients to receive the recommended dosages of such targeted therapies. The eruption responds well to some acne therapies and xerosis can be controlled by standard emollients. Here we present an overview of the treatment options for skin reactions that are available today, and evaluate some of the ways in which the treatment of such EGFR-inhibitor-related skin reactions may be improved in the future. Evidence-based studies are needed to determine the best way to manage these effects.

The PTEN gene is a tumor-suppressor gene that is inactivated in several types of human tumors. The loss of PTEN expression has been supported as a prognostic marker. Using immunohistochemical analysis, we retrospectively analyzed PTEN expression in specimens from 53 patients with completely resected stage I non-small cell lung cancer (NSCLC) for whom clinical follow-up data were available. Seven of the 53 specimens showed a total lack of staining for PTEN. No statistically significant relationship could be found between PTEN expression and clinicopathological parameters. Although genetic alterations of the PTEN gene are rare in NSCLC, loss of PTEN protein is not an uncommon event in early-stage NSCLC (13.2%). Here, we also report that the level of PTEN protein expression is not an independent prognostic marker in early-stage NSCLC.

Surgery remains the standard treatment of rectal cancer. The risk of local recurrence is still a serious problem with an incidence of between 15 and 45%. This depends on the initial TNM stage and the surgical technique. In order to optimally improve local control and survival of the patients, radiotherapy has become an unavoidable adjuvant treatment in specific situations.For locally advanced cancers (T3 or T4), pre-surgical radiotherapy followed by curative surgery is the standard treatment because of the improvement in global survival and good local control that has recently been confirmed. With radiotherapy it is also possible to schedule conservative sphincter surgery in the case of low rectal lesions and permit surgery of initially inoperable lesions. THE CONCOMITANT ASSOCIATION OF RADIOTHERAPY AND CHEMOTHERAPY DURING THE PRE-SURGICAL PERIOD: In rare cases in which the tumour stage was underestimated in the pre-surgical controls, post-surgical concomitant radio-chemotherapy is required. In cases in which surgery was performed first line, in the presence of histological factors of poor prognosis, post-surgical radio-chemotherapy is warranted. In the United States, the reference chemotherapy used in this association is 5 FU in continuous intravenous infusion. In the rare cases of contraindication for surgery, exclusive concomitant radio-chemotherapy is an appropriate solution, even if no treatment has been validated in this indication. Palliative surgery can be proposed in supplement: usually a colostomy or, more rarely excision using the endorectal route.Exclusive radio-chemotherapy has only demonstrated interest in the palliative treatment of inoperable loco-regional relapses that have already undergone radiation or in metastatic stages as in colon cancers. Currently post-surgical chemotherapy is recommended in stage III cancer of the rectum as in colon cancers at the same stage.

Study of the antitumour effects of erythropoietin on metastatic renal cell carcinoma.After giving their informed consent, 20 patients with histologically proven metastatic renal cell carcinoma received subcutaneous recombinant erythropoietin three times a day at a dose of 150 IU/kg when haemoglobin was less than or equal to 12 g/dL or 75 IU/kg when haemoglobin was higher than 12 g/dL. Treatment was continued for a minimum of 8 weeks before reassessment and was continued thereafter, except in the case of progression or excessive toxicity. A staging assessment was performed every 8 weeks and the response was assessed on the basis of WHO criteria. A clinical and laboratory assessment was performed every two months to evaluate toxicity, graded according to the WHO scale. All but one of the patients had received immunotherapy or chemotherapy prior to inclusion in the study.One complete response (12 months), one partial response (8 months), two minor responses, 10 cases of stabilisation and 6 cases of progression were observed. 15 patients received treatment at full doses. In 5 patients, the duration of treatment was reduced before the 8 weeks initially defined because of tumour progression in one patient and because of haemoglobin persistently greater than 15 g/dL in 4 other patients. Adverse effects consisted of 1 case of moderate headache, 2 cases of transient bone pain, and 1 case of transient hypertension.Erythropoietin exerts a moderate antitumour effect which needs to be confirmed by a phase II trial of first-line treatment in selected patients.

One hundred nine previously untreated patients with small cell lung cancer were treated for five consecutive days with 20 mg/m2/day of cisplatin and 600 mg/m2/day of 5-fluorouracil. One cycle of chemotherapy was administered every three weeks. The patients received a median number of three cycles. Then they were transferred to CAE chemotherapy. A 77% overall response rate (95% confidence interval of 0.70-0.85) was observed after initial cisplatin-5FU treatment. Twenty-three complete responses (21%) and 62 partial responses (56%) were obtained. In cerebral metastases the response rate was high at 91% (21 out of 23), with 43% complete responses. In the limited forms, statistical survival at 1 year was 25%. A Grade 3-4 thrombocytopaenia was observed in 10 patients (9%) and a Grade 2-3 leukopaenia in four patients. Three patients suffered from a Grade 2 cardiac toxicity. The cisplatin-5-fluorouracil combination demonstrates promising initial response rate in small cell lung cancers. Its main interest is in its important action on cerebral metastases and its moderate haematological toxicity.