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International audience; CONTEXT AND AIMS:Breast cancer prognosis and predictive biomarkers development would allow sparing some patients from chemotherapy or identifying patients for whom chemotherapy would be indicated. In this context, in 2009, the French National Cancer Institute, a National Health and Science Agency dedicated to cancer, in collaboration with the French society of senology and breast pathology (SFSPM) published a report on the assessment of the prognostic and the predictive clinical validity of tissular biomarkers, uPA/PAI-1, Oncotype DX™ and MammaPrint(®), in breast cancer management. They concluded that only the uPA/PAI-1 prognosis value reached the highest level of evidence (LOE I according to Hayes 1998 classification). In 2012, it was decided to update this report since new data have emerged and because information disparities among clinicians have been identified. This article aims to present the main conclusions together with the levels of evidence associated with those conclusions.METHODS:The updating process was based on literature published since 2009 appraisal and on multidisciplinary and independent experts' opinion. The levels of evidence (LOE) used are those of the classification defined by Simon in 2009 (updated Hayes 1998 classification): LOE IA and LOE IB: high level of evidence; LOE IIB and LOE IIC: intermediate level of evidence; LOE IIIC and LOE IV-VD: low level of evidence.CONCLUSIONS:Among patients without lymph-node involvement, uPA/PAI-1, invasion process biomarkers, reach the highest level of evidence for 10 years recurrence free survival prognosis (LOE IA according to Simon). The predictive value to anthracyclins chemotherapy remains to be confirmed. Oncotype DX™ and MammaPrint(®) prognosis and predictive value do not reach the LOE I level. This updating' process confirms the 2009 levels of evidence for all the three biomarkers prognosis value. Besides, concerning Oncotype DX™ and MammaPrint(®), new data do not allow to conclude neither to their complementary clinical information to other clinicopathological existing biomarkers nor to a favorable cost-efficiency ratio in therapeutic decision making and this because of the methodological weakness and uncertainty that are identified in the selected studies. Practically, beyond the prognosis and predictive biomarkers validity, the clinical utility of a new biomarker for chemotherapy indication depends on its clinical added information with regard to validated biomarkers (HR, HER2 and Ki67) and to clinicopathological parameters. Since they are the sole validated biomarkers of the invasion process, uPA/PAI-1 could complete clinical information of other clinicopathological factors and consequently could confer an added clinical value. However, data concerning the impact of this information on chemotherapy clinical indication are lacking.Copyright © 2014. Published by Elsevier Masson SAS.; IntroductionDans le cancer du sein, le développement des marqueurs biologiques pronostiques ou prédictifs a pour objectif de mieux identifier les patientes pour lesquelles un traitement par chimiothérapie pourrait être évité ou a contrario indiqué. Dans ce contexte, en 2009, l’Institut national du cancer (INCa), agence sanitaire et scientifique de l’État chargée de coordonner les actions de lutte contre le cancer, avait publié en partenariat avec la Société française de sénologie et de pathologie mammaire un rapport sur l’état des connaissances relatives aux biomarqueurs uPA/PAI-1, Oncotype DX™ et MammaPrint® dans la prise en charge du cancer du sein. Ce rapport avait montré que seule la valeur pronostique d’uPA/PAI-1 atteignait le plus haut niveau de preuve (LOE I selon la grille de Hayes 1998). En 2012, devant la parution de nouvelles publications et la divergence des messages diffusés sur les signatures moléculaires, il a été décidé d’actualiser le rapport de 2009. Cet article présente les principales conclusions accompagnées de leurs niveaux de preuve.MéthodeLe processus de mise à jour s’est appuyé sur l’analyse des données publiées depuis la recherche bibliographique de 2009, complétée par l’avis d’un groupe de travail multidisciplinaire indépendant. Les niveaux de preuve employés sont ceux de la classification définie par Simon en 2009 (grille de Hayes 1998 après mise à jour) : LOE IA et LOE IB : niveau de preuve élevé ; LOE IIB and LOE IIC : niveau de preuve intermédiaire ; LOE IIIC and LOE IV-VD : niveau de preuve faible.ConclusionsChez les patientes sans envahissement ganglionnaire (pN0), uPA/PAI-1, marqueurs d’invasion, ont un niveau de preuve élevé (LOE IA selon Simon) pour la valeur pronostique de la survie sans récidive à 10 ans. Il reste à confirmer leur valeur prédictive de réponse aux anthracyclines. Pour Oncotype DX™ et MammaPrint®, les valeurs pronostique et prédictive n’ont pas atteint à ce jour le niveau de preuve LOE I. Ce travail confirme les niveaux de preuve précédemment établis dans le rapport de 2009. Par ailleurs, les données ne permettent pas de conclure à une valeur ajoutée de Oncotype DX™ et MammaPrint® par rapport aux outils existants. Les données médico-économiques ne permettent pas de statuer sur le rapport coût/efficacité des stratégies utilisant ces tests dans la décision thérapeutique compte tenu d’un niveau de qualité insuffisant pour la plupart des études et d’une forte incertitude mise en évidence par les quelques études bien menées. En pratique, au-delà des niveaux de preuve attribuables à la valeur pronostique et prédictive d’un biomarqueur, l’utilité clinique d’un nouveau marqueur dans l’aide à la prescription d’une chimiothérapie repose sur sa valeur ajoutée par rapport aux marqueurs validés (RH, HER2 et les marqueurs de prolifération comme Ki67) et aux critères anatomo-cliniques. Puisqu’ils sont les seuls marqueurs validés à témoigner du processus d’invasion, uPA/PAI-1 peuvent apporter une information complémentaire et donc avoir une valeur ajoutée par rapport aux marqueurs existants. Les données de la littérature manquent pour apprécier le poids de cette valeur ajoutée dans la décision de prescrire ou non une chimiothérapie.

Cutaneous radionecrosis and osteoradionecrosis are severe complications of the radiotherapy which can arise after a variable free interval. The loss of substance is frequently associated with a peripheral radiodermatitis and stays an infectious front door exposing patients to a sepsis. The reference treatment remains surgical and consists in realizing the debridment of necrosis tissues associated with flap in order to cover the soft tissus defect. The purpose of our study is to estimate efficiency and tolerance of management radionecrosis thoracique by muscle-sparing latissimus dorsi flap (MSLD).We realized a study on a series of cases of thoracic radionecrosis with costal exposure covered by MSLD. Fat transfer into peripheral radiodermitis was performed at the same time surgical. Efficiency and tolerance surgery were estimated. The duration of the postoperative antibiotic treatment was estimated. The complications (hematoma, infection, cutaneous suffering, necrosis, seroma, radionecrosis relapse) were screened. The follow-up was realized by the same surgeon.Seven patients managed by the same surgeon were included, They had radionecrosis after radiotherapy for processing adjuvanting of mastectomy after breast cancer. The average age was 66 years (from 61 to 76 years). The average time of hospitalisation was of four days. The average follow-up was of six months. The average treatment of the antibiotic treatment was four weeks. We didn't notice any complications and any recurrence of the radionecrosis. We noticed one dorsal collection (30 cm(3)) 15 days after surgical procedure for one patient. The follow-up showed a stable and good quality cutaneous cover in six months postoperative.MSLD flap is reliable and reproducible to cover moderate thoracic defect. The surgical parage-wash has a fundamental importance to avoid any infectious complication. The management of the thoracic radionecrosis is complex and multidisciplinary. In conclusion, MSLD flap seems to be an elegant surgical alternative insuring a custom-made optimal cover with a reduction of the morbidity of the site donor.

The proteome, first formalized in 1995, designs all the proteins expressed by the genome of a cell, tissu, or organ at a defined time. Proteomic analysis leads to a description of the regulation of gene expression by the study of proteins and of their post-translational modifications. Proteomic analysis is based on three technologies: 1) Two-dimensional electrophoresis allowing the separation of thousands of proteins from a single mixture; 2) mass spectrometry allowing the characterization of picoquantities of polypeptides and providing data on post-translational modifications; 3) Bioinformatic which is required for the quantification of protein level and for the constitution of databases of protein expression profiles. Complementing the methods of the genomics, the use of proteomic analysis is widely spreading in the fields of fundamental biology, biomedicine and pharmacology for the identification of new biological markers and therapeutic targets.

Oncological complete surgery of retroperitoneal tumours may require segmental resection of part of the invaded inferior vena cava. The aim of this retrospective study was to assess whether reconstruction of the inferior vena cava is necessary and presents any advantage.This study included four patients who underwent partial resection of the inferior vena cava invaded by a retroperitoneal tumour, without reconstruction. Tumours were one renal cancer, one malignant phaeochromocytoma, one malignant retroperitoneal histiofibroma and one undifferentiated retroperitoneal carcinoma. The resection was located at the level of the renal confluence, associated with right nephrectomy, in 3 patients, and above this confluence, at the level of the retrohepatic inferior vena cava in 1 patient.Only one case of transient acute renal failure was observed during the postoperative course. One patient developed right deep vein thrombosis after three months and another one after 30 months. One patient died from cancer recurrence after 19 months. The other 3 patients were alive with anticoagulant therapy and without sequelae after 3, 6 and 15 years.

The aim of this prospective study was to evaluate, in a series of 350 gastric adenocarcinomas, the evolution of their clinical and histological features and the evolution of their surgical management.From 1970 to 1996, 350 patients with gastric carcinoma (cardiac cancer excluded) were operated on in the same center. Mean age was 68.8 years and the sex ratio 1:4. These patients were divided into three groups which were analysed and compared (group 1 operated on between 1970 and 1988, group 2 between 1979 and 1987, group 3 between 1988 and 1996).Antropyloric cancer was the most common (56% in group 3). Tumor size decreased but there were in group 3 more undifferentiated tumors (54.2%) and more tumors with lymph node involvement (72%). Stage III and IV tumors were still common (70% in group 3) and early gastric cancer incidence very low (9.9%). After 1980, surgical management was more radical, with more total gastrectomies and larger lymph node dissections. Adjuvant intraoperative and postoperative radiotherapy has been associated since 1985. Postoperative mortality rate decreased (13.8% in group 1 vs 6.1% in group 3) (P = 0.04) as did the postoperative morbidity rate (31.8% in group 1 vs 17.5% in group 3). The five-year actuarial survival rate was respectively 18.9% and 39.2% for groups 1 and 2 (P = 0.003); it was respectively 59.8% and 43.6% for all patients treated by adjuvant radiotherapy and for those with lymph node involvement.Prognosis of gastric adenocarcinoma is still poor. A more radical surgical treatment did not increase the postoperative morbidity rate, but increased the survival rate. New adjuvant treatments including radiotherapy have to be evaluated in order to improve the prognosis.

The BRCA1 gene modification is responsible for an autosomal dominant syndrome of inherited early onset breast and/or ovarian cancer. This gene is estimated to account for almost half of inherited breast cancers and three quarters of inherited breast/ovarian cancers. This suggests that about 1 out of 500 women may carry BRCA1 mutation. The BRCA1 gene was isolated by positional cloning in 1994. More than 100 different mutations have been found in the germline of affected individuals. We looked by systematic sequencing at BRCA1 germline mutations in 36 patients treated at the Centre Oscar-Lambret for breast and/or ovarian cancer and that belonged to high risk families. We have found 24 mutations: 9 true mutations inducing modifications of the BRCA1 protein (BRCA1+), 5 mutations with unknown consequences on the BRCA1 protein and 10 mutations corresponding to polymorphisms that had been previously described. All the BRCA1+ cases had a HPG3 tumor. The median age of discovery and the receptor positivity percentage are lower in hereditary breast cancer than in the standard population of the breast cancers treated in our center. Consequently, BRCA1 mutations are associated to parameters thought to be of bad prognosis.

We investigated binding characteristics of bFGF in membranes prepared from 4 human breast cancer cell lines (MCF-7, T-47D, BT-20 and MDA-MB-231) and 38 primary breast cancer biopsies. Results of competitive binding experiments were analysed using the "Ligand" program to determine binding site concentrations and affinities. bFGF mitogenic activity was also measured by [3H]-thymidine incorporation into DNA of breast cancer cell lines. The presence of high-affinity binding sites was demonstrated in each cell type (Kd: 0.5 nM). The presence of these high-affinity binding sites was confirmed by saturation experiments. A second class of low-affinity binding sites was detected in the 2 hormono-independent cells (BT-20: Kd = 2.9 nM; MDA-MB-231: Kd = 2.7 nM). bFGF stimulated the proliferation of MCF-7, 7-47D, BT-20 and not of MDA-MB-231 cell lines. In breast cancer biopsies, binding sites were detectable in 36/38 cases; high-affinity binding sites (Kd1 nM) were present in 19/39 cases and low-affinity binding sites (Kd2 nM) were present in 29/36 cases (the 2 classes of binding sites were present in 12 biopsies). No relation between FGF binding sites and node involvement nature or grade of tumor was evidenced. Negative correlations (Spearman test) were found between total bFGF binding site concentrations and estradiol receptor concentrations (P = 0.05) or progesterone receptor concentrations (P = 0.009). The demonstrations of 1), bFGF specific binding sites in breast cancer membranes; and 2) bFGF growth stimulation of some breast cancer cell lines, indicate that this factor could be involved in the growth of most breast cancers, and could act (among other factors) directly on the growth of cancer cells.

Prolactin (PRL) has an important peripheral role to play in female reproductive function. This hormone, in physiological concentrations, is necessary so that the follicle can mature properly. It also helps the maturation of oocytes and is essential for the physiological action of the corpus luteum so that progesterone production can be stimulated. It inhibits its catabolism and is responsible for keeping up the numbers of LH and oestradiol receptors. It works through the intermediary of prolactin receptors which are localised on the granulosa cells. The mechanism is through immuno-cytochemistry and it can be distinguished biochemically (Ka = 0.5 10(10) M). Probably, when levels are high it upsets follicular maturation by inhibiting the biosynthesis of the oestrogens and also by stimulating the secretion in the granulosa cells of a substance that inhibits oocyte maturation: and prolactin exercises a luteolytic action by stimulating the catabolism of the hormone and lessening the numbers of LH receptors. On the other and, there are high concentrations of PRL in amniotic fluid. As endometrial cells undergo the phenomenon of decidualization they produce PRL which is identical biochemically with the pituitary hormone. Certain steroids seem to regulate this synthesis of PRL. This hormone must play a role in fetal osmoregulation through the intermediary of prolactin receptors.

EGF membrane receptors (R-EGF) were assayed in 65 human breast cancer biopsies. The Scatchard analysis of the binding of 125I-EGF indicated a single class of sites with an apparent dissociation constant of 1 nM. Fourty-eight percent of the tumors are R-EGF positive (specific binding greater than 1% of total radioactivity), the level of receptors reaching 14%. We have not observed any relationship between R-EGF and hormone receptors (estradiol, progesterone and prolactin) or clinical and histological characteristics of the tumor. Taking into account the role of EGF in growth of some human breast cancer epithelial cells culture and the possible production of R-EGF by oncogenes, these results suggest that R-EGF could be an uindependent biochemical marker of human breast cancer.

Prolactin plays a peripheral role in male reproductive function just as it does in female function. Prolactin, through the medium of immunocytochemistry acts on testicular steroidogenesis through prolactin receptors which are sited on the Leydig cells. It alters the number of LH receptors and therefore the sensitivity of the testis to central stimulation and equally interferes with androgen synthesis. In the areas of physiological concentration the principal effect seems to be to stimulate secretion of testosterone by keeping up the number of LH receptors; but when there is acute hyperprolactinaemia, testosterone secretion is lowered or perhaps not changed at all because of a "post-receptor effect", in spite of there being larger numbers of LH receptors. The direct effect of prolactin on spermatogenesis has not yet been worked out and the results that have been obtained are controversial. Prolactin exerts a direct stimulating effect on the growth of prostatic cells working synergistically with testosterone through specific prolactin receptors. It could play a role in certain cancers of the prostate.