Recent years have seen the emergence of new molecules for the treatment of patients with metastatic cutaneous melanoma, with significant benefits in terms of survival and the opening of new therapeutic perspectives. In addition, many techniques are currently being developed for locoregional treatment of metastatic sites. Management of metastatic melanoma is thus fast-changing and is marked by innovative therapeutic approaches. However, the availability of these new treatments has prompted debate among healthcare professionals concerning their use and their place in therapeutic strategy.

Since the discovery of the structure of DNA in 1953 by Watson and Crick, our understanding of the genetic causes and the regulations involved in tumor development have hugely increased. The important amount of research developed since then has led to the development of gene therapy, which specifically targets and treats cancer cells by interacting with, and correcting their genetic material. This study is a review of the most accomplished research using gene therapy aimed at treating malignant ophthalmologic diseases, and focuses more specifically on uveal melanoma and retinoblastoma. Such approaches are remarkable regarding the efficiency and the cellular targeting specificity. However, gene therapy-based treatments are so recent that many long-term interrogations subsist. The majority of the reviewed studies are conducted in vitro or in murine models, thereby requiring several years before the resulting therapies become part of the daily ophthalmologists' arsenal. However, the recent spectacular developments based on advanced scientific knowledge justify an up-to-date review that would benefit the ophthalmologist community.

We report the case of a 20 years old woman with unusual acute myeloid leukemia t(8;21). Cytological, phenotypic and cytogenetic investigations showed a divergence from those of the literature as well as data for the last 12 LA to t(8;21) supported in the service.

During two centuries, advances in medicine and medical research have helped to understand the pathophysiology of chronic myelogenous leukemia (CML). This hematologic malignancy is a unique model of oncogenesis where a single molecular hit, causing cell proliferation and survival, was identified. The chromosomal abnormality first highlighted by P. Nowell and D. Hungerford in 1960, and characterized as the reciprocal translocation t(9;22)(q34;q11), the Philadelphia chromosome, discovered in leukemic cells, by J. Rowley in 1973. At the end of the 20th century, the contribution of molecular biology techniques was crucial by the discovery of the BCR-ABL1 hybrid oncogene derived from the t(9;22), responsible for the translation of an aberrant protein tyrosine kinase. This BCR-ABL1 kinase deregulates signaling pathways that control normal cell cycle and survival in primitive hematopoietic cells and is thus responsible for malignant cell accumulation observed in CML. It was then only necessary to develop a targeted treatment adapted to this molecular hit. Recently, tyrosine kinase inhibitors, by their specific inhibitory activity of BCR-ABL, have revolutionized the treatment of CML, allowing rates of haematological, cytogenetic and molecular responses never seen to date, and has significantly improved the overall survival and the quality of life of patients.

The proliferation, survival and mobility of cancer cells are maintained by deregulation of signaling pathways, including RAS/RAF/MEK/ERK/. Constitutive activation of these pathways is a common event in human cancers. It is most often caused by mutations or altered expression of genes encoding key players in this pathway. Knowledge of the mechanisms of intracellular activation of these circuits has led to the development of inhibitory molecules aimed at limiting tumor growth. These molecules have been developed through extensive clinical trials marked by impressive therapeutic successes that have pioneered the concept of targeted therapies, leading to a new paradigm of cancer therapy. However, despite these remarkable clinical responses, particularly in metastatic melanoma, poorly understood drug resistance mechanisms eventually come into play. Resistance mechanisms associated with secondary mutations in B-RAF seem to be infrequent in melanomas, while those related to target circumvention are more common. The latter include an increase in the expression and regulation of PDGF and IGF-l receptors, and secondary mutations in the N-RAS, COT or MEK genes. They involve the activation pathways MEK/ERK and/or PI3K/AKT in conditions in which the target is inhibited. Resistance may also be explained by deregulation of the MEK/ERK pathway, leading to the expression of genes that had been subject to negative feedback. Moreover, the tumor microenvironment, through the secretion of soluble factors, stimulates signaling pathways that can compensate for MEK/ERK pathway inhibition. Lastly, combinations of MEK/ERK inhibition and immunotherapy open the way to new therapeutic strategies designed to circumvent drug resistance. Without calling into question the concept of "oncogenic addiction", in which alteration of a single gene is responsible for persistence of the tumoral phenotype, these findings call for a rethink on the use of targeted therapies. A more integrated view of the tumor including its microenvironment, will no doubt be necessary.

Skin cancer is the most common human malignancy, and sunlight exposure is known to play a role in its genesis. Ultraviolet B (UVB) (300-320 nm) has long been considered responsible for the skin damage underlying these cancers, whereas the toxicity of UVA (320-400 nm) has been largely overlooked The intimate mechanisms of photocarcinogenicity remain poorly understood, but UV-induced DNA damage appears to be a major initiating event. Cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) photoproducts (6-4PPs) are the main dimeric lesions induced by UVB, whereas the genotoxic effects of UVA have long been attributed to oxidative damage, the main lesion being the oxidized base 8-oxo-7,8dihydroguanine (8-oxoGua). However; powerful new techniques for analyzing DNA damage (the Comet assay, and especially HPLC-MSIMS) have demonstrated that UVA irradiation mainly triggers the formation of CPDs, especially CPD-TT both in cell models and in total human skin. A direct photochemical process is currently thought to account for CPD induction by UVA. The multilayer structure of the epidermis protects against UVB-induced dipyrimidine lesions in total skin but offers only weak protection against UVA. In addition, repair efficiency is undermined by UVA. CPDs, the main DNA lesions induced by UVA in total skin (which is more permeable to UVA), are inefficiently repaired CPDs have strong mutagenic potential, and recent studies clearly show that CPDs, rather than 8-Oxo-Gua, are the main mutagenic photoproducts induced by UVA. The UV signature of induced mutations is characterized by transitions from C to T or CC to TT in dipyrimidine sequences. These mutations target the p53, patched 1 and SMO genes in carcinomas, and the PTEN RAC1, PPP6C, STK19 and PPP6C genes in melanomas of exposed skin. UVA also mainly induces CPDs in melanocytes, in amounts similar to those observed in keratinocytes, demonstrating that melanin does not prevent CPD formation. In contrast, UVA induces far more abundant 8-oxo-Gua production in melanocytes than in keratinocytes. Thus, under UVA irradiation, oxidative stress contributes more to DNA damage in melanocytes than in keratinocytes. In addition, baseline oxidative damage (in the absence of UVA) is already higher in melanocytes. The photosensitizer may be melanin itself. This is supported by a recent study based on a murine model, in which melanoma induction was shown to require both UVA and the presence of melanin in melanocytes, and is associated with oxidative damage to DNA. Conversely, UVB was found to initiate melanoma through a direct, pigment-independent pathway. Thus, two wavelength-dependent pathways can induce melanoma, with melanin playing an unexpected role. Constitutive pigmentation is very effective in preventing UV-induced damage, and a clear correlation can thus be found between, on the one hand, the amount of CPD TT produced by both UVB and UVA and, on the other hand, the minimum erythematous dose and the phototype. Melanin is thus a two-facetted molecule, protecting the skin when its synthesis is complete and when melanosomes take on their nucleus-protective geometric configuration in keratinocytes, but having a pro-oxidant action when only partially polymerized and exposed to UV Repeated exposure of volunteer skin shows that a tan induced by UVB provides little protection against DNA damage caused by subsequent exposure, while tanning with UVA provides no protection at all. Yet both UVB and UVA provoke DNA damage. All these recent data highlight the potential role of UVA in skin carcinogenesis, and reinforce epidemiological studies showing an increased risk of melanoma among users of tanning lamps, particularly young women. The decision by the International Agency for Research on Cancer to classify UVA and tanning devices as group 1 carcinogens, and the opinion issued by the French National Academy of Medicine on tanning booths, therefore appear to be fully justified. The use of tanning salons should be permanently banned

Ovarian granulosa cell tumors (TGO) are rare neoplasms. They arise from sex cord stromal cells of the ovaries. They are characterized by their slow natural history, and their tendency to relapse long time after the initial diagnosis. Complete staging surgery of the disease is the cornerstone of treatment. Chemotherapy is indicated for localized tumors with a high risk of recurrence, and for recurrent or advanced tumors. Prolonged follow-up is recommended.

Gastric signet ring cell carcinoma (GSRC) is a distinct entity. Their incidence is increasing. The pathologist plays a central role in the identification of this entity. Diagnosis is based on an adenocarcinoma containing a majority of signet ring cells (above 50 %). The prognosis of GSRC is the same as gastric adenocarcinoma while GSRC appeared more aggressive. Signet ring cells present a low sensitivity to chemotherapy. This review aimed to discuss the histological, the prognostic and the therapeutic aspect of this entity.

DNA sequencing technologies have advanced at an exponential rate in recent years: the first human genome was sequenced in 2001 after many years of effort by dozens of international laboratories at a cost of tens of millions of dollars, while in 2013 a genome can be sequenced within 24 hours for a few hundred dollars (exome sequencing takes only a few hours). More and more hospital laboratories are acquiring new high-throughput sequencing devices ("next-generation sequencers", NGS), allowing them to analyze tens or hundreds of genes, or even the entire exome. This is having a major impact on medical concepts and practices, especially with respect to genetics and oncology. This ability to search for mutations simultaneously in a large number of genes is finding applications in the diagnosis of Mendelian diseases (including at birth), routine screening for heterozygotes, and pre-conception diagnosis. NGS is now sufficiently sensitive to analyze circulating fetal DNA in maternal blood (cell-free fetal DNA, cffDNA), enabling applications such as non invasive diagnosis of fetal sex (and X-linked diseases), fetal rhesus among rhesus-negative women, trisomy and, in the near future, Mendelian mutations. Data on multifactorial diseases are still preliminary, but it should soon be possible to identify "strong" factors of genetic predisposition that have so far been beyond the scope of genome-wide association studies (GWAS). In the field of constitutional oncogenetics, NGS can also be used for simultaneous analysis of genes involved in " hereditary " cancers (21 breast cancer genes, 6 colon cancer genes, etc.). More generally, NGS can identify all genomic abnormalities (deletions, translocations, mutations) in a given malignant tissue (hemopathy or solid tumor), and has the potential to distinguish between important mutations (those that drive tumor progression) from " bystander " or accessory mutations, and also to identify "druggable" mutations amenable to targeted therapies (e.g. imatinib and Bcr/Abl rearrangement; verumafemib and the BRAF V600E mutation). Systematic sequencing of all the genes involved in drug metabolism and responsiveness will lead to individualized pharmacogenetics. Finally, sequencing of the tumoral and constitutional genomes, identfication of somatic mutations, and detection of pharmacogenetic variants will open up the era of personalized medicine. The first results of these targeted therapeutic indications show a gain in the duration of remission and survival, although the cost-effectiveness of these approaches remains to be determined. Finally, this huge capacity for genome sequencing raises a number of regulatory and ethical issues.

This article is a selection of the most significant developments in the field of pediatric dermatology through an analysis of the articles published between October 2012 and October 2013. In the field of vascular anomalies, propranolol remains a topic of interest for infantile hemangiomas. New clinical concepts appear in the field of vascular malformations in parallel to genetic progress in this area. New epidemiological data or new pathophysiological concepts apply to atopic dermatitis. Congenital or atypical nevi of the child benefit from genetic progress or improvement of clinical knowledge. Although rare, melanoma of the child concerns by its increasing incidence and its misleadingclinical characteristics. Other data reported here relate to infectious skin of the child, morpheas, neurofibromatosis type 1, psoriasis and other commonly seen dermatoses in children.

Pituitary adenomas define slow growing tumors developing from anterior pituitary. Most often benign, their treatment and subsequent management are based on transphenoidal surgery and/or medical therapy, generally without difficulties in clinical practice. However, 2 clinicopathological situations, more or less intricated, may considerably complicate the management of these tumors and the patient health condition. Firstly, when the tumor is characterized by an usual aggressive behaviour with a possible extension within the cavernous sinus and a high risk of recurence after well- conducted treatment. Otherwise, in some cases of resistant prolactinomas and somatotropinomas, the specific medical treatment may be unsuccessful for controlling the hormonal hypersecretion and/or the tumoral growth, with subsequent complex therapeutic approach. Progress that have been made in the understanding of aggressive as well as in resistant- to- treatment pituitary tumors, both in histopathology and molecular fields, may constitue new tools for improving knowledge on the profile of these atypical tumors and optimizing their management.

Cutaneous melanoma is a malignant tumor with a high metastatic potential. If an early treatment is associated with a favorable outcome, the prognosis of metastatic melanoma remains poor. Advances in molecular characterization of cancers, notably the discovery of BRAF gene mutations in metastatic melanoma, allowed to the recent development of targeted therapies against mutated BRAF protein. Despite high tumor response rates observed in clinical trials, these new drugs are associated with frequent secondary tumor resistance occurrence and paradoxical carcinogenic side effects. The cellular and molecular mechanisms of these carcinogenic side effects and secondary resistance are not yet fully elucidated and are actually intensely studied. This review of the literature focus on the mechanisms of these carcinogenic side effects and on the tumor resistance associated with anti-BRAF targeted therapies.

Germ-cell tumours (GCTs) are the most common type of cancer in young men. Since the late 1970s, disseminated GCT have been a paradigm for curable metastatic cancer and metastatic GCTs are highly curable with cisplatin-based chemotherapy followed by surgical resection of residual masses. Patients' prognosis is currently assessed using the International Germ-Cell Consensus Classification (IGCCC) and used to adapt the burden of chemotherapy. Approximately 20% of patients still do not achieve cure after first-line cisplatin-based chemotherapy, and need salvage chemotherapy (high dose or standard dose chemotherapy). Clinical stage I testicular cancer is the most common presentation and different strategies are proposed: adjuvant therapies, surgery or surveillance. During the last three decades, clinical trials and strong international collaborations lead to the development of a consensus in the management of GCTs.

Abiraterone acetate has increased the overall survival of patients with metastatic castration-resistant prostate cancer. However, despite an initial response to treatment, many patients develop resistance to the drug. In this paper we present different hypotheses that may explain the emergence of resistance.

To investigate the role of imaging procedures in the diagnosis of synchronous bilateral breast cancer (SBBC) PATIENTS AND METHODS: The patient group consisted of consecutive women undergoing managed for SBBC in our institution between January 2006 and July 2012. We defined SBBC as bilateral breast tumors diagnosed simultaneously or up to 3 months after initial diagnosis. Clinical data included comorbidities, BMI (kg/m(2)), preoperative breast imaging modalities used and their findings.