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Objective: When treated with anticancer therapies, a number of issues are raised for older patients such as physical needs (coping with symptoms and side-effects) or psychological needs. Geriatric tailored interventions addressing these needs may be effective in terms of improving quality of life of our patients. Methods: A systematic review was performed in September 2017 in MEDLINE. All reports assessing older patients with cancer care needs in the context of anticancer systemic therapy were reviewed. Results: A total of 357 articles were analyzed. From these, 35 studies were included in the analysis. Compared to younger patients, the elderly had less supportive care needs. While older patients asked for less information than their younger counterparts, they still requested information on diagnosis, seriousness of the disease, chances of cure, spread of the disease, recovery, courses of illness, possible consequences, treatment procedures, treatment options, possible side effects and how to deal with them, and what they could do in daily life. When taking into consideration the various needs as assessed by the "Supportive Care Needs Survey", physical and daily living were the most frequently reported needs with emphasis on nutrition, coping with physical symptoms, dealing with side effects of treatment, and performing usual physical tasks and activities. Conclusion: Information demand seemed moderate but a great deal of attention was paid to nutrition and well-being. (C) 2018 Elsevier Ltd. All rights reserved.

International audience; The ability to stratify patients using a set of biomarkers, which predict that toxicity risk would allow for radiotherapy (RT) modulation and serve as a valuable tool for precision medicine and personalized RT. For patients presenting with tumors with a low risk of recurrence, modifying RT schedules to avoid toxicity would be clinically advantageous. Indeed, for the patient at low risk of developing radiation-associated toxicity, use of a hypofractionated protocol could be proposed leading to treatment time reduction and a cost-utility advantage. Conversely, for patients predicted to be at high risk for toxicity, either a more conformal form or a new technique of RT, or a multidisciplinary approach employing surgery could be included in the trial design to avoid or mitigate RT when the potential toxicity risk may be higher than the risk of disease recurrence. In addition, for patients at high risk of recurrence and low risk of toxicity, dose escalation, such as a greater boost dose, or irradiation field extensions could be considered to improve local control without severe toxicities, providing enhanced clinical benefit. In cases of high risk of toxicity, tumor control should be prioritized. In this review, toxicity biomarkers with sufficient evidence for clinical testing are presented. In addition, clinical trial designs and predictive models are described for different clinical situations.

International audience; CD146 (MUC-18, MCAM) expression on cancer cells correlates with cancer progression and a bad prognosis in several tumors, including melanoma and pancreatic tumors. Deciphering the mechanism mediating the CD146 role in cancer is essential for generating new therapeutic strategies. We found that CD146 expression in cancer cells is associated with a secretion of soluble CD146 (sCD146) that constitutes an active player in tumor development. Indeed, sCD146 induces the overexpression of its binding protein, angiomotin, on both endothelial and cancer cells and promotes both paracrine effects on angiogenesis and autocrine effects on cancer cells proliferation and survival. These last effects are mediated in part through the induction and phosphorylation of c-myc in cancer cells. In mice models xenografted with human CD146-positive melanoma or pancreatic cancer cells, administration of a novel monoclonal antibody specifically targeting sCD146, but not its membrane form, successfully suppresses tumor vascularization and growth. Our findings demonstrate that sCD146 secreted by CD146-positive tumors mediates important pro-angiogenic and pro-tumoral effects. Targeting sCD146 with a novel neutralizing antibody could thus constitute an innovative therapeutic strategy for the treatment of CD146-positive tumors.

International audience; Moonlighting proteins are a subset of multifunctional proteins characterized by their multiple, independent, and unrelated biological functions. We recently set up a large-scale identification of moonlighting proteins using a protein-protein interaction (PPI) network approach. We established that 3% of the current human interactome is composed of predicted moonlighting proteins. We found that disease-related genes are over-represented among those candidates. Here, by comparing moonlighting candidates to non-candidates as groups, we further show that (7 they are significantly involved in more than one disease, (ii) they contribute to complex rather than monogenic diseases, (iii) the diseases in which they are involved are phenotypically different according to their annotations, finally, (iv) they are enriched for diseases pairs showing statistically significant comorbidity patterns based on Medicare records. Altogether, our results suggest that some observed comorbidities between phenotypically different diseases could be due to a shared protein involved in unrelated biological processes.

Introducción: El cáncer se ha convertido en las últimas décadas en una de las principales causas de muerte en todo el mundo. La búsqueda para la prevención efectiva, se ha convertido en una prioridad para la ciencia básica y clínica. Los polifenoles del vino se han propuesto como terapia alternativa para inducir o mantener la remisión del cáncer. Objetivo: Revisar las evidencias científicas publicadas sobre el cáncer y la eficacia de la terapia con suplementos dietarios (especialmente polifenoles del vino). Material y métodos: Se ha realizado una extensa búsqueda de publicaciones científicas en las principales bases de datos electrónicas especializadas: NBCI, Elsevier, Scielo, Scirus y Science Direct. Resultados y Discusión: Se han reunido resultados de trabajos realizados in vitro y en animales de laboratorio en los que se pone de manifiesto el efecto de los polifenoles del vino (especialmente, el resveratrol) en el control de la apoptosis celular de diferentes tipos de cánceres mediante un aumento de las especies reactivas de oxígeno, así como también el retardo en el crecimiento de las mismas. El consumo de vino regular y moderado (uno o dos vasos al día) se asocia con la disminución de la incidencia de enfermedad cardiovascular, la hipertensión, la diabetes, y ciertos tipos de cáncer, como el de colon, el de mama, el de pulmón, o de próstata. Sin embargo, las evidencias científicas a cerca de los efectos protectores del resveratrol son insuficientes. Conclusiones: Los resultados publicados hasta la fecha referentes al rol de los polifenoles del vino en la prevención del cáncer contribuyen al mejor conocimiento y entendimiento de las modificaciones moleculares del cáncer. Los polifenoles del vino ha demostrado un papel significativo como antioxidante y prooxidante en el cáncer, aunque son necesarias más investigaciones en humanos. Introduction: Cancer has become in the recent decades one of the leading causes of death worldwide. The search for effective prevention has become a priority for the basic and clinical science. Wine polyphenols have been proposed as alternative therapy for induction and on maintaining remission of cancer. Objective: To review current scientific evidence of cancer and the efficacy of dietary supplement therapy (especially wine polyphenols). Materials and Methods: Extensive search of scientific publications was performed in specialized electronic databases: NBCI, Elsevier, Scielo, Scirus and Science Direct. Results and discussion: Results from in vitro and laboratory animals experiments demonstrate that wine polyphenols controls the cell apoptosis of different type of cancers through out the increase of reactive oxygen species, and decrease of cell growth. Different studies have shown that regular and moderate wine consumption (one or two glasses for day) is associated with decreased incidence of cardiovascular disease, hypertension, diabetes, and certain cancers, such as colon, breast, lung, or prostate. However, more scientific evidences are needed to strength the effect of resveratrol in controlling cancer. Conclusions: A better knowledge and understanding of the wine polyphenol role in cancer disease patients is possible with the current published results. The wine polyphenols plays a significant role as antioxidant and prooxidant in cancer, although more extensive studies are required to determine the clinical significance in humans.

The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high-dose radiation-induced proctitis. Irradiated pigs received repeated intravenous administrations of autologous bone marrow-derived MSCs. Immunostaining and real-time polymerase chain reaction analysis were used to assess the MSCs' effect on inflammation, extracellular matrix remodeling, and angiogenesis, in radiation-induced anorectal and colon damages. In humans, as in pigs, rectal overexposure induces mucosal damage (crypt depletion, macrophage infiltration, and fibrosis). In a pig model, repeated administrations of MSCs controlled systemic inflammation, reduced in situ both expression of inflammatory cytokines and macrophage recruitment, and augmented interleukin-10 expression in rectal mucosa. MSC injections limited radiation-induced fibrosis by reducing collagen deposition and expression of col1a2/col3a1 and transforming growth factor-β/connective tissue growth factor, and by modifying the matrix metalloproteinase/TIMP balance. In a pig model of proctitis, repeated injections of MSCs effectively reduced inflammation and fibrosis. This treatment represents a promising therapy for radiation-induced severe rectal damage.

Bosetti, Cristina Rosato, Valentina Polesel, Jerry Levi, Fabio Talamini, Renato Montella, Maurizio Negri, Eva Tavani, Alessandra Zucchetto, Antonella Franceschi, Silvia Corrao, Giovanni La Vecchia, Carlo eng Research Support, Non-U.S. Gov't 2012/04/24 06:00 Nutr Cancer. 2012;64(5):643-51. doi: 10.1080/01635581.2012.676141. Epub 2012 Apr 20.; International audience; Diabetes has been associated to the risk of a few cancer sites, though quantification of this association in various populations remains open to discussion. We analyzed the relation between diabetes and the risk of various cancers in an integrated series of case-control studies conducted in Italy and Switzerland between 1991 and 2009. The studies included 1,468 oral and pharyngeal, 505 esophageal, 230 gastric, 2,390 colorectal, 185 liver, 326 pancreatic, 852 laryngeal, 3,034 breast, 607 endometrial, 1,031 ovarian, 1,294 prostate, and 767 renal cell cancer cases and 12,060 hospital controls. The multivariate odds ratios (OR) for subjects with diabetes as compared to those without-adjusted for major identified confounding factors for the cancers considered through logistic regression models-were significantly elevated for cancers of the oral cavity/pharynx (OR = 1.58), esophagus (OR = 2.52), colorectum (OR = 1.23), liver (OR = 3.52), pancreas (OR = 3.32), postmenopausal breast (OR = 1.76), and endometrium (OR = 1.70). For cancers of the oral cavity, esophagus, colorectum, liver, and postmenopausal breast, the excess risk persisted over 10 yr since diagnosis of diabetes. Our data confirm and further quantify the association of diabetes with colorectal, liver, pancreatic, postmenopausal breast, and endometrial cancer and suggest forthe first time that diabetes may also increase the risk of oral/pharyngeal and esophageal cancer.

Les fistules vésico-uréthro-rectales après traitement du cancer de la prostate sont rares, mais posent un problème de prise en charge thérapeutique difficile. Denombreuses approches chirurgicales ont été décrites et aucune à l?heure actuelle ne fait consensus. Le but de cette étude était de présenter notre expérience avecl'utilisation de deux techniques chirurgicales, afin de déterminer la meilleure stratégie thérapeutique. L'étude rétrospective des dossiers de 16 patients, ayant été pris en charge pour cure d?une FVUR entre septembre 2003 et 2010 a été menée. Onze patients ont bénéficié d?un abord trans-rectal selon York et Mason en première intention, 8 patients ont bénéficié d'une interposition de Gracilis dont 3 après échec de l'abord trans-rectal. Les fistules sont apparues dans les suites d'une prostatectomie radicale pour 14 cas, et de curiethérapie pour 2 cas. Avec une médiane de suivi de 40 mois, on observe une fermeture de la fistule chez 15 des 16 patients, soit 94%. La DMS avec une interposition musculaire est de 10,2 jours. La technique de York et Mason permet d'obtenir un pourcentage de guérison de 73% en première intention avec une durée moyenne de séjour courte (9,8 jours) et un taux de complication post-opératoire faible. A notre sens, elle doit être utilisée de première intention dans la prise en charge des FVUR. L'interposition de muscle gracilis pourrait être réservée aux échecs du York et Mason et aussi à la prise en charge initiale des fistules survenant en terrain irradié, pour interposer des tissus bien vascularisés

Transcription factors (TFs) bind specifically to discrete regions of mammalian genomes called cis-regulatory elements. Among those are enhancers, which play key roles in regulation of gene expression during development and differentiation. Despite the recognized central regulatory role exerted by chromatin in control of TF functions, much remains to be learned regarding the chromatin structure of enhancers and how it is established. Here, we have analyzed on a genomic-scale enhancers that recruit FOXA1, a pioneer transcription factor that triggers transcriptional competency of these cis-regulatory sites. Importantly, we found that FOXA1 binds to genomic regions showing local DNA hypomethylation and that its cell-type-specific recruitment to chromatin is linked to differential DNA methylation levels of its binding sites. Using neural differentiation as a model, we showed that induction of FOXA1 expression and its subsequent recruitment to enhancers is associated with DNA demethylation. Concomitantly, histone H3 lysine 4 methylation is induced at these enhancers. These epigenetic changes may both stabilize FOXA1 binding and allow for subsequent recruitment of transcriptional regulatory effectors. Interestingly, when cloned into reporter constructs, FOXA1-dependent enhancers were able to recapitulate their cell type specificity. However, their activities were inhibited by DNA methylation. Hence, these enhancers are intrinsic cell-type-specific regulatory regions of which activities have to be potentiated by FOXA1 through induction of an epigenetic switch that includes notably DNA demethylation.

Prostate cancer is the most common cancer found in the male population, with nearly 60 000 new cases in 2007, and the second most fatal cancer, just after lung cancer, with 9 200 deaths in France in the same year. It is a real challenge for public health. The coming of PSA in the nineties has completely changed the way to care for this cancer : it has made it possible to perform the follow up of the treated patients, but moreover to diagnose the cancer when curable, i.e. when it is still limited to the prostate gland and when it can be eradicated. For the first time, and after a long time of confusion, common recommendations for both official and scientific authorities are going to be established regarding its screening, mainly thanks to the contribution, in March 2009, of the greatest prospective and randomized study ever realized about the impact of the screening by PSA, the ERSPC study. From its discovery to the recommendations on screening, from the determination of the "cutoff" to the various biological forms, from the over-diagnostic to the over-treatment, the PSA, as the main tool for prostate cancer screening, has always caused some controversy. Recently, the POC tests have placed the PSA on the list of biological indicators, that they can nowadays dose quickly, precisely and reliably from an ordinary capillary blood test. The PSAwatch ®, already commercialized in Great Britain, seems to be promising. Does the future of screening by total PSA measurement depend on the POC tests ?; Le cancer de la prostate, qui représente le premier cancer de l'homme avec près de 60000 nouveaux cas en 2007 et le second cancer en terme de mortalité avec 9200 morts la même année en France derrière le cancer du poumon, représente un véritable enjeu de santé publique. L'avènement du PSA dans les années 90 a révolutionné l'histoire de la prise en charge de ce cancer, en permettant le suivi des patients traités, mais surtout en permettant de le diagnostiquer à un stade curable, quand il est encore limité à la glande prostatique et qu'il peut être éradiqué. Pour la première fois, et après une longue période de confusion, des recommandations communes entre les autorités officielles et scientifiques vont être établies concernant son dépistage, notamment grâce à l'apport notable, en mars 2009, de la plus grande étude prospective randomisée jamais réalisée sur l'impact du dépistage par le PSA, l'ERSPC. De sa découverte aux recommandations sur le dépistage, de la détermination du "cut-off" aux différentes formes biologiques, du surdiagnostic au surtraitement, le PSA comme outil principal du dépistage du cancer de prostate a toujours été au centre de la polémique. Récemment, les POC tests ont inscrit le PSA sur la liste des marqueurs biologiques qu'ils dosent dorénavant avec rapidité, précision et fiabilité à partir d un simple prélèvement capillaire. Le PSAwatch ®, déjà commercialisé en Grande-Bretagne, s'annonce prometteur. L'avenir du dépistage par le dosage du PSA total leur appartient-il ?

Pathogenesis of multiple myeloma is associated with an aberrant expression of pro-proliferative, pro-angiogenic and bone-metabolism-modifying factors by malignant plasma cells. Given the frequently long time span from diagnosis of early-stage plasma cell dyscrasias to overt myeloma and the mostly low proliferation rate of malignant plasma cells, we hypothesize these to similarly express a novel class of inhibitory factors of potential prognostic relevance. Bone morphogenic proteins (BMPs) represent possible candidates as they inhibit proliferation, stimulate bone formation and have an effect on the survival of cancer patients. We assessed the expression of BMPs and their receptors by Affymetrix DNA microarrays (n=779) including CD138-purified primary myeloma cell samples (n=635) of previously untreated patients. BMP6 is the only BMP expressed by malignant and normal plasma cells. Its expression is significantly lower in proliferating myeloma cells, myeloma cell lines or plasmablasts. BMP6 significantly inhibits the proliferation of myeloma cell lines, survival of primary myeloma cells and in vitro angiogenesis. A high BMP6 expression in primary myeloma cell samples delineates significantly superior overall survival for patients undergoing high-dose chemotherapy independent of conventional prognostic factors (International Staging System (ISS) stage, beta(2) microglobulin). Oncogene (2009) 28, 3866-3879; doi:10.1038/onc.2009.257; published online 31 August 2009

La radiothérapie appartient à l'arsenal thérapeutique des cancers localisés de la prostate. La radiothérapie conformationnelle est une adaptation géométrique de la balistique à la forme de la tumeur. L'objectif est de délivrer une dose élevée d'irradiation au volume tumoral en épargnant, au maximum, les tissus sains de proximité. Son utilité a été démontrée en termes de réduction de la toxicité et d'amélioration de la qualité de vie. Par ailleurs, cette innovation technologique autorise l'escalade de dose, dans l'espoir d'améliorer le contrôle local, dont onconnaît le rôle essentiel sur la survie. La faisabilité de cette escalade de dose a étéfavorablement évaluée (pas de majoration des toxicités aiguës et chroniques). Le bénéfice, en termes de contrôle clinique et biologique, semble se confirmer.L'avènement des Histogrammes Dose-Volume (HDV) permet l'étude de la relation entre la dose reçue par les tissus sains et la survenue de complications. Des recommandations de dose sont progressivement établies pour les organes à risque.La précision balistique requiert un équipement hautement spécialisé. Elle impose la définition précise des volumes à irradier, ainsi que l'évaluation, la réduction et la prise en compte des incertitudes de repositionnement et de mobilité interne.Malheureusement, la conformation des isodoses autour du volume cible reste imparfaite. La radiothérapie conformationnelle avec modulation d'intensité a été développée pour permettre la réalisation d'isodoses concaves. Elle améliore la couverture du volume cible. Pour certains, elle améliore l'épargne des tissus sains, autorisant l'espoir d'une réduction de la toxicité. Nous proposons une comparaison dosimétrique des techniques conventionnelle et conformationnelle avec ou sans modulation d'intensité, aux doses de 70 et 80 Gy. La supériorité des techniques conformationnelles est établie à dose conventionnelle. En escalade de dose, la modulation d'intensité assure une meilleure couverture du volmue cible , tout enrespectant les contraintes de dose aux organes à risque. Nous proposons, également, l'étude rétrospective des résultats préliminaires de l'expérienceNancéienne en radiothérapie conformationnelle dans le traitement curatif du cancer localisé de la prostate. Nous comparons ces résultats à ceux obtenus antérieurement, dans le même centre, par radiothérapie conventionnelle. Nos conclusions vont dans le sens de la littérature. Ainsi, la réduction de taille des champs ne s'accompagne pas d'une réduction de l'efficacité thérapeutique, à doses conventionnelles. Par ailleurs, elle permet l'escalade de dose au delà de70 Gy, sans majoration des toxicités. Cette augmentation de la dose s'accompagne d'un bénéfice thérapeutique en termes de contôle clinique et/ou biologique.